CA2672267A1 - Arylsulfanyl compounds and compositions for delivering active agents - Google Patents
Arylsulfanyl compounds and compositions for delivering active agents Download PDFInfo
- Publication number
- CA2672267A1 CA2672267A1 CA002672267A CA2672267A CA2672267A1 CA 2672267 A1 CA2672267 A1 CA 2672267A1 CA 002672267 A CA002672267 A CA 002672267A CA 2672267 A CA2672267 A CA 2672267A CA 2672267 A1 CA2672267 A1 CA 2672267A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- aryl
- mmol
- active agent
- insulin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000013543 active substance Substances 0.000 title claims abstract description 97
- 239000000203 mixture Substances 0.000 title claims abstract description 52
- 125000005163 aryl sulfanyl group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 159
- 229940124447 delivery agent Drugs 0.000 claims description 123
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 87
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- -1 postaglandins Proteins 0.000 claims description 40
- 229920000669 heparin Polymers 0.000 claims description 33
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 32
- 102000004877 Insulin Human genes 0.000 claims description 29
- 108090001061 Insulin Proteins 0.000 claims description 29
- 229940125396 insulin Drugs 0.000 claims description 29
- 125000002947 alkylene group Chemical group 0.000 claims description 28
- 229960002897 heparin Drugs 0.000 claims description 28
- 239000000843 powder Substances 0.000 claims description 28
- 239000000122 growth hormone Substances 0.000 claims description 22
- 108010020326 Caspofungin Proteins 0.000 claims description 19
- 241001465754 Metazoa Species 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 229960000730 caspofungin acetate Drugs 0.000 claims description 16
- OGUJBRYAAJYXQP-IJFZAWIJSA-N vuw370o5qe Chemical compound CC(O)=O.CC(O)=O.C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 OGUJBRYAAJYXQP-IJFZAWIJSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 12
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 229960001319 parathyroid hormone Drugs 0.000 claims description 12
- 239000000199 parathyroid hormone Substances 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 239000003055 low molecular weight heparin Substances 0.000 claims description 11
- 229940127215 low-molecular weight heparin Drugs 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 125000000732 arylene group Chemical group 0.000 claims description 10
- 229940088597 hormone Drugs 0.000 claims description 10
- 239000005556 hormone Substances 0.000 claims description 10
- 229940079322 interferon Drugs 0.000 claims description 10
- 239000003488 releasing hormone Substances 0.000 claims description 10
- 108060001064 Calcitonin Proteins 0.000 claims description 9
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims description 9
- 239000012634 fragment Substances 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- 102000055006 Calcitonin Human genes 0.000 claims description 8
- 102000003951 Erythropoietin Human genes 0.000 claims description 8
- 108090000394 Erythropoietin Proteins 0.000 claims description 8
- 229940105423 erythropoietin Drugs 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 8
- 108060003199 Glucagon Proteins 0.000 claims description 7
- 102000051325 Glucagon Human genes 0.000 claims description 7
- 102000018997 Growth Hormone Human genes 0.000 claims description 7
- 108010051696 Growth Hormone Proteins 0.000 claims description 7
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 7
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 7
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 claims description 7
- 229960000958 deferoxamine Drugs 0.000 claims description 7
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 7
- 229960004666 glucagon Drugs 0.000 claims description 7
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 7
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 claims description 6
- 229960004015 calcitonin Drugs 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 241000283690 Bos taurus Species 0.000 claims description 5
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 claims description 5
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 claims description 5
- 102000014150 Interferons Human genes 0.000 claims description 5
- 108010050904 Interferons Proteins 0.000 claims description 5
- 229940028334 follicle stimulating hormone Drugs 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- 235000013772 propylene glycol Nutrition 0.000 claims description 5
- 229960004063 propylene glycol Drugs 0.000 claims description 5
- 229960001028 zanamivir Drugs 0.000 claims description 5
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 claims description 5
- WKEMJKQOLOHJLZ-UHFFFAOYSA-N Almogran Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CS(=O)(=O)N1CCCC1 WKEMJKQOLOHJLZ-UHFFFAOYSA-N 0.000 claims description 4
- 101800000414 Corticotropin Proteins 0.000 claims description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 4
- 229930105110 Cyclosporin A Natural products 0.000 claims description 4
- 108010036949 Cyclosporine Proteins 0.000 claims description 4
- 108010029961 Filgrastim Proteins 0.000 claims description 4
- 102000004547 Glucosylceramidase Human genes 0.000 claims description 4
- 108010017544 Glucosylceramidase Proteins 0.000 claims description 4
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 claims description 4
- 229920001499 Heparinoid Polymers 0.000 claims description 4
- 102000002265 Human Growth Hormone Human genes 0.000 claims description 4
- 108010000521 Human Growth Hormone Proteins 0.000 claims description 4
- 239000000854 Human Growth Hormone Substances 0.000 claims description 4
- 102000000589 Interleukin-1 Human genes 0.000 claims description 4
- 108010002352 Interleukin-1 Proteins 0.000 claims description 4
- 108010002350 Interleukin-2 Proteins 0.000 claims description 4
- 102000000588 Interleukin-2 Human genes 0.000 claims description 4
- 102400000050 Oxytocin Human genes 0.000 claims description 4
- 101800000989 Oxytocin Proteins 0.000 claims description 4
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims description 4
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 claims description 4
- 108010059993 Vancomycin Proteins 0.000 claims description 4
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims description 4
- 108010004977 Vasopressins Proteins 0.000 claims description 4
- 102000002852 Vasopressins Human genes 0.000 claims description 4
- 229960002133 almotriptan Drugs 0.000 claims description 4
- 239000003429 antifungal agent Substances 0.000 claims description 4
- 229940121375 antifungal agent Drugs 0.000 claims description 4
- 239000000427 antigen Substances 0.000 claims description 4
- 108091007433 antigens Proteins 0.000 claims description 4
- 102000036639 antigens Human genes 0.000 claims description 4
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 4
- 230000001746 atrial effect Effects 0.000 claims description 4
- 229960001265 ciclosporin Drugs 0.000 claims description 4
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 claims description 4
- 229960000258 corticotropin Drugs 0.000 claims description 4
- 229960000265 cromoglicic acid Drugs 0.000 claims description 4
- 229930182912 cyclosporin Natural products 0.000 claims description 4
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 4
- 229960002472 eletriptan Drugs 0.000 claims description 4
- 229960004177 filgrastim Drugs 0.000 claims description 4
- 229960002284 frovatriptan Drugs 0.000 claims description 4
- SIBNYOSJIXCDRI-SECBINFHSA-N frovatriptan Chemical compound C1=C(C(N)=O)[CH]C2=C(C[C@H](NC)CC3)C3=NC2=C1 SIBNYOSJIXCDRI-SECBINFHSA-N 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims description 4
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims description 4
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 claims description 4
- 239000002554 heparinoid Substances 0.000 claims description 4
- 229940025770 heparinoids Drugs 0.000 claims description 4
- 229940047124 interferons Drugs 0.000 claims description 4
- 150000002632 lipids Chemical class 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229960005254 naratriptan Drugs 0.000 claims description 4
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 claims description 4
- ITIXDWVDFFXNEG-JHOUSYSJSA-N olcegepant Chemical compound C([C@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCN(CC1)C=1C=CN=CC=1)NC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C1=CC(Br)=C(O)C(Br)=C1 ITIXDWVDFFXNEG-JHOUSYSJSA-N 0.000 claims description 4
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 claims description 4
- 229960001723 oxytocin Drugs 0.000 claims description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 4
- 229920001184 polypeptide Polymers 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 229960000425 rizatriptan Drugs 0.000 claims description 4
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 claims description 4
- 229960003165 vancomycin Drugs 0.000 claims description 4
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 4
- 229960003726 vasopressin Drugs 0.000 claims description 4
- 239000011782 vitamin Substances 0.000 claims description 4
- 229930003231 vitamin Natural products 0.000 claims description 4
- 235000013343 vitamin Nutrition 0.000 claims description 4
- 229940088594 vitamin Drugs 0.000 claims description 4
- 229920002567 Chondroitin Polymers 0.000 claims description 3
- 229920000045 Dermatan sulfate Polymers 0.000 claims description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 3
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 claims description 3
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 3
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims description 3
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 108091030071 RNAI Proteins 0.000 claims description 3
- 102100022831 Somatoliberin Human genes 0.000 claims description 3
- 101710142969 Somatoliberin Proteins 0.000 claims description 3
- 102000005157 Somatostatin Human genes 0.000 claims description 3
- 108010056088 Somatostatin Proteins 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- HZLAWYIBLZNRFZ-VXGBXAGGSA-N cphpc Chemical compound OC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1[C@@H](C(O)=O)CCC1 HZLAWYIBLZNRFZ-VXGBXAGGSA-N 0.000 claims description 3
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 claims description 3
- 150000002258 gallium Chemical class 0.000 claims description 3
- 230000009368 gene silencing by RNA Effects 0.000 claims description 3
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 claims description 3
- 108010068072 salmon calcitonin Proteins 0.000 claims description 3
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims description 3
- 229960000553 somatostatin Drugs 0.000 claims description 3
- 229960003708 sumatriptan Drugs 0.000 claims description 3
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 claims description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 claims description 2
- 229960003856 argatroban Drugs 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 102000013275 Somatomedins Human genes 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 101001011741 Bos taurus Insulin Proteins 0.000 claims 2
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims 2
- 101000741445 Homo sapiens Calcitonin Proteins 0.000 claims 2
- 108010005991 Pork Regular Insulin Proteins 0.000 claims 2
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 claims 2
- 229910052733 gallium Inorganic materials 0.000 claims 2
- 229940045644 human calcitonin Drugs 0.000 claims 2
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 2
- JDJALSWDQPEHEJ-LMVCGNDWSA-N x4853 Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 JDJALSWDQPEHEJ-LMVCGNDWSA-N 0.000 claims 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims 1
- JYIKNQVWKBUSNH-QWDBRQCVSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)CC(C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-QWDBRQCVSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 64
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 189
- 125000003118 aryl group Chemical group 0.000 description 173
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 108
- 239000000243 solution Substances 0.000 description 104
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 95
- 235000019441 ethanol Nutrition 0.000 description 73
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 71
- 239000000047 product Substances 0.000 description 71
- 235000011118 potassium hydroxide Nutrition 0.000 description 63
- 229940093932 potassium hydroxide Drugs 0.000 description 63
- 238000001914 filtration Methods 0.000 description 61
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 54
- 239000007787 solid Substances 0.000 description 47
- 229910052717 sulfur Inorganic materials 0.000 description 47
- 238000006243 chemical reaction Methods 0.000 description 44
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 238000003756 stirring Methods 0.000 description 36
- 239000002253 acid Substances 0.000 description 33
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 239000012299 nitrogen atmosphere Substances 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 239000008194 pharmaceutical composition Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 16
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 16
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 16
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 13
- 159000000000 sodium salts Chemical class 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 229920000642 polymer Polymers 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 10
- 229940126639 Compound 33 Drugs 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- DXBULVYHTICWKT-UHFFFAOYSA-N ethyl 6-bromohexanoate Chemical compound CCOC(=O)CCCCCBr DXBULVYHTICWKT-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000004888 barrier function Effects 0.000 description 8
- 239000008363 phosphate buffer Substances 0.000 description 8
- 238000013222 sprague-dawley male rat Methods 0.000 description 8
- DSCJETUEDFKYGN-UHFFFAOYSA-N 2-Methoxybenzenethiol Chemical compound COC1=CC=CC=C1S DSCJETUEDFKYGN-UHFFFAOYSA-N 0.000 description 7
- PWOBDMNCYMQTCE-UHFFFAOYSA-N 2-chlorobenzenethiol Chemical compound SC1=CC=CC=C1Cl PWOBDMNCYMQTCE-UHFFFAOYSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- UBTQVPMVWAEGAC-UHFFFAOYSA-N ethyl 8-bromooctanoate Chemical compound CCOC(=O)CCCCCCCBr UBTQVPMVWAEGAC-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 6
- NIFAOMSJMGEFTQ-UHFFFAOYSA-N 4-methoxybenzenethiol Chemical compound COC1=CC=C(S)C=C1 NIFAOMSJMGEFTQ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940125833 compound 23 Drugs 0.000 description 6
- 229940125878 compound 36 Drugs 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- FQTIYMRSUOADDK-UHFFFAOYSA-N ethyl 3-bromopropanoate Chemical compound CCOC(=O)CCBr FQTIYMRSUOADDK-UHFFFAOYSA-N 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 238000003305 oral gavage Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- VVIUKYOXYSWCOF-UHFFFAOYSA-N (4-acetylphenyl)thiourea Chemical compound CC(=O)C1=CC=C(NC(N)=S)C=C1 VVIUKYOXYSWCOF-UHFFFAOYSA-N 0.000 description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
- CQJDYPZUDYXHLM-UHFFFAOYSA-N 3-chlorobenzenethiol Chemical compound SC1=CC=CC(Cl)=C1 CQJDYPZUDYXHLM-UHFFFAOYSA-N 0.000 description 5
- 208000013016 Hypoglycemia Diseases 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 208000001132 Osteoporosis Diseases 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000001766 physiological effect Effects 0.000 description 5
- 238000003825 pressing Methods 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 4
- NHAUBUMQRJWWAT-UHFFFAOYSA-N 2,5-dimethylbenzenethiol Chemical compound CC1=CC=C(C)C(S)=C1 NHAUBUMQRJWWAT-UHFFFAOYSA-N 0.000 description 4
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical compound OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-N 0.000 description 4
- QMVAZEHZOPDGHA-UHFFFAOYSA-N 3-methoxybenzenethiol Chemical compound COC1=CC=CC(S)=C1 QMVAZEHZOPDGHA-UHFFFAOYSA-N 0.000 description 4
- DOFIAZGYBIBEGI-UHFFFAOYSA-N 3-sulfanylphenol Chemical compound OC1=CC=CC(S)=C1 DOFIAZGYBIBEGI-UHFFFAOYSA-N 0.000 description 4
- CQQSQBRPAJSTFB-UHFFFAOYSA-N 4-(bromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CBr)C=C1 CQQSQBRPAJSTFB-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 206010027452 Metastases to bone Diseases 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 206010052779 Transplant rejections Diseases 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000003238 esophagus Anatomy 0.000 description 4
- AFRWBGJRWRHQOV-UHFFFAOYSA-N ethyl 5-bromopentanoate Chemical compound CCOC(=O)CCCCBr AFRWBGJRWRHQOV-UHFFFAOYSA-N 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 210000004283 incisor Anatomy 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- QIULLHZMZMGGFH-UHFFFAOYSA-N 2,5-dichlorobenzenethiol Chemical compound SC1=CC(Cl)=CC=C1Cl QIULLHZMZMGGFH-UHFFFAOYSA-N 0.000 description 3
- WCOCCXZFEJGHTC-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(CBr)C=C1 WCOCCXZFEJGHTC-UHFFFAOYSA-N 0.000 description 3
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 3
- WJTZZPVVTSDNJJ-UHFFFAOYSA-N 2-fluorobenzenethiol Chemical compound FC1=CC=CC=C1S WJTZZPVVTSDNJJ-UHFFFAOYSA-N 0.000 description 3
- OKIHXNKYYGUVTE-UHFFFAOYSA-N 4-Fluorothiophenol Chemical compound FC1=CC=C(S)C=C1 OKIHXNKYYGUVTE-UHFFFAOYSA-N 0.000 description 3
- VZXOZSQDJJNBRC-UHFFFAOYSA-N 4-chlorobenzenethiol Chemical compound SC1=CC=C(Cl)C=C1 VZXOZSQDJJNBRC-UHFFFAOYSA-N 0.000 description 3
- BXAVKNRWVKUTLY-UHFFFAOYSA-N 4-sulfanylphenol Chemical compound OC1=CC=C(S)C=C1 BXAVKNRWVKUTLY-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108010039627 Aprotinin Proteins 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000037147 Hypercalcaemia Diseases 0.000 description 3
- 208000020221 Short stature Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940126545 compound 53 Drugs 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 230000000148 hypercalcaemia Effects 0.000 description 3
- 208000030915 hypercalcemia disease Diseases 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 238000007726 management method Methods 0.000 description 3
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 3
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 3
- 230000009469 supplementation Effects 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 description 2
- ZYZCALPXKGUGJI-DDVDASKDSA-M (e,3r,5s)-7-[3-(4-fluorophenyl)-2-phenyl-5-propan-2-ylimidazol-4-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C=1C=C(F)C=CC=1N1C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C(C)C)N=C1C1=CC=CC=C1 ZYZCALPXKGUGJI-DDVDASKDSA-M 0.000 description 2
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 2
- FUJSJWRORKKPAI-UHFFFAOYSA-N 2-(2,4-dichlorophenoxy)acetyl chloride Chemical compound ClC(=O)COC1=CC=C(Cl)C=C1Cl FUJSJWRORKKPAI-UHFFFAOYSA-N 0.000 description 2
- DCXXCTCEJFBLPD-UHFFFAOYSA-N 2-(2,5-dichlorophenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC(Cl)=CC=C1Cl DCXXCTCEJFBLPD-UHFFFAOYSA-N 0.000 description 2
- KBDQNOMRWXPWIY-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC=C(Cl)C(Cl)=C1 KBDQNOMRWXPWIY-UHFFFAOYSA-N 0.000 description 2
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 2
- HNJZDPKMMZXSKT-UHFFFAOYSA-N 3,4-dichlorobenzenethiol Chemical compound SC1=CC=C(Cl)C(Cl)=C1 HNJZDPKMMZXSKT-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 2
- ZDEUGINAVLMAET-UHFFFAOYSA-N 3-fluorobenzenethiol Chemical compound FC1=CC=CC(S)=C1 ZDEUGINAVLMAET-UHFFFAOYSA-N 0.000 description 2
- DAEUMJMOLYOQFB-UHFFFAOYSA-N 4-(3-methylphenoxy)butanoic acid Chemical compound CC1=CC=CC(OCCCC(O)=O)=C1 DAEUMJMOLYOQFB-UHFFFAOYSA-N 0.000 description 2
- MQWMQIPSRHKJDQ-UHFFFAOYSA-N 4-[(2-hydroxyphenyl)sulfanylmethyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CSC1=CC=CC=C1O MQWMQIPSRHKJDQ-UHFFFAOYSA-N 0.000 description 2
- WLILBDMBJNDKRT-UHFFFAOYSA-N 4-[(4-chlorophenyl)sulfanylmethyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CSC1=CC=C(Cl)C=C1 WLILBDMBJNDKRT-UHFFFAOYSA-N 0.000 description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 2
- CPZPJNOURRTLQS-UHFFFAOYSA-N 8-(4-hydroxyphenyl)sulfanyloctanoic acid Chemical compound OC(=O)CCCCCCCSC1=CC=C(O)C=C1 CPZPJNOURRTLQS-UHFFFAOYSA-N 0.000 description 2
- YKYODTNPCSIYMW-UHFFFAOYSA-N 8-(4-methoxyphenyl)sulfanyloctanoic acid Chemical compound COC1=CC=C(SCCCCCCCC(O)=O)C=C1 YKYODTNPCSIYMW-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000007514 Herpes zoster Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 2
- 208000010191 Osteitis Deformans Diseases 0.000 description 2
- 208000027868 Paget disease Diseases 0.000 description 2
- 108010088847 Peptide YY Proteins 0.000 description 2
- 102100029909 Peptide YY Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000036693 Thrombopoietin Human genes 0.000 description 2
- 108010041111 Thrombopoietin Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000002460 anti-migrenic effect Effects 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229960003034 caspofungin Drugs 0.000 description 2
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 229940125936 compound 42 Drugs 0.000 description 2
- 229940127271 compound 49 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000002641 glycemic effect Effects 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 229960004525 lopinavir Drugs 0.000 description 2
- 208000027202 mammary Paget disease Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000001582 osteoblastic effect Effects 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 238000010242 retro-orbital bleeding Methods 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229940108519 trasylol Drugs 0.000 description 2
- 210000001635 urinary tract Anatomy 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- FOCBRFMNUQOMCY-LPWJVIDDSA-N (1r,3s,4r)-3-[(1s)-1-acetamido-2-ethylbutyl]-4-(diaminomethylideneamino)cyclopentane-1-carboxylic acid Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1C[C@@H](C(O)=O)C[C@H]1N=C(N)N FOCBRFMNUQOMCY-LPWJVIDDSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- YSIBYEBNVMDAPN-CMDGGOBGSA-N (e)-4-oxo-4-(3-triethoxysilylpropylamino)but-2-enoic acid Chemical compound CCO[Si](OCC)(OCC)CCCNC(=O)\C=C\C(O)=O YSIBYEBNVMDAPN-CMDGGOBGSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- NUBQKPWHXMGDLP-UHFFFAOYSA-N 1-[4-benzyl-2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1h-inden-1-yl)amino]-5-oxopentyl]-n-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide;sulfuric acid Chemical compound OS(O)(=O)=O.C1CN(CC(O)CC(CC=2C=CC=CC=2)C(=O)NC2C3=CC=CC=C3CC2O)C(C(=O)NC(C)(C)C)CN1CC1=CC=CN=C1 NUBQKPWHXMGDLP-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- SMUFIMYWZKLBNX-UHFFFAOYSA-N 10-(3-hydroxyphenyl)sulfanyldecanoic acid Chemical compound OC(=O)CCCCCCCCCSC1=CC=CC(O)=C1 SMUFIMYWZKLBNX-UHFFFAOYSA-N 0.000 description 1
- FPHJEQWPBXGFGN-UHFFFAOYSA-N 10-(3-methoxyphenyl)sulfanyldecanoic acid Chemical compound COC1=CC=CC(SCCCCCCCCCC(O)=O)=C1 FPHJEQWPBXGFGN-UHFFFAOYSA-N 0.000 description 1
- BOOYZWVVNCFLRI-UHFFFAOYSA-N 10-(4-hydroxyphenyl)sulfanyldecanoic acid Chemical compound OC(=O)CCCCCCCCCSC1=CC=C(O)C=C1 BOOYZWVVNCFLRI-UHFFFAOYSA-N 0.000 description 1
- DRTNNSJQBCUQML-UHFFFAOYSA-N 2-(2-chlorophenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC=CC=C1Cl DRTNNSJQBCUQML-UHFFFAOYSA-N 0.000 description 1
- BSTQAHSCLFITHV-UHFFFAOYSA-N 2-(2-fluorophenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC=CC=C1F BSTQAHSCLFITHV-UHFFFAOYSA-N 0.000 description 1
- QMOKVFCLFRLSTN-UHFFFAOYSA-N 2-(3-chlorophenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC=CC(Cl)=C1 QMOKVFCLFRLSTN-UHFFFAOYSA-N 0.000 description 1
- JDPSVGKEJKYOAZ-UHFFFAOYSA-N 2-(3-fluorophenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC=CC(F)=C1 JDPSVGKEJKYOAZ-UHFFFAOYSA-N 0.000 description 1
- GWWHVKUWRKYHAA-UHFFFAOYSA-N 2-(3-hydroxyphenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC=CC(O)=C1 GWWHVKUWRKYHAA-UHFFFAOYSA-N 0.000 description 1
- HQEROVXUKINLPI-UHFFFAOYSA-N 2-(4-fluorophenyl)sulfanylacetic acid Chemical compound OC(=O)CSC1=CC=C(F)C=C1 HQEROVXUKINLPI-UHFFFAOYSA-N 0.000 description 1
- WPRFIGTZKOUYRL-UHFFFAOYSA-N 2-(4-methoxyphenyl)sulfanylacetic acid Chemical compound COC1=CC=C(SCC(O)=O)C=C1 WPRFIGTZKOUYRL-UHFFFAOYSA-N 0.000 description 1
- QSVVQODFPIRITB-UHFFFAOYSA-N 2-(6-morpholin-4-ylhexoxy)phenol Chemical compound OC1=CC=CC=C1OCCCCCCN1CCOCC1 QSVVQODFPIRITB-UHFFFAOYSA-N 0.000 description 1
- SZWUGRUMUPFLHH-UHFFFAOYSA-N 2-(8-morpholin-4-yloctoxy)phenol Chemical compound OC1=CC=CC=C1OCCCCCCCCN1CCOCC1 SZWUGRUMUPFLHH-UHFFFAOYSA-N 0.000 description 1
- ZYGIZBFKXXWBKD-UHFFFAOYSA-N 2-[4-[(2-methoxyphenyl)sulfanylmethyl]phenyl]acetic acid Chemical compound COC1=CC=CC=C1SCC1=CC=C(CC(O)=O)C=C1 ZYGIZBFKXXWBKD-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- NYUNDDKGPQCWPL-UHFFFAOYSA-N 3-(2-chlorophenyl)sulfanylpropanoic acid Chemical compound OC(=O)CCSC1=CC=CC=C1Cl NYUNDDKGPQCWPL-UHFFFAOYSA-N 0.000 description 1
- LBNJHWGKGWWFGN-UHFFFAOYSA-N 3-(3-chlorophenyl)sulfanylpropanoic acid Chemical compound OC(=O)CCSC1=CC=CC(Cl)=C1 LBNJHWGKGWWFGN-UHFFFAOYSA-N 0.000 description 1
- ITKMQBLIGHHZQS-UHFFFAOYSA-N 4-(2-chlorophenyl)sulfanylbutanoic acid Chemical compound OC(=O)CCCSC1=CC=CC=C1Cl ITKMQBLIGHHZQS-UHFFFAOYSA-N 0.000 description 1
- KALOQPLSFUOZFB-UHFFFAOYSA-N 4-(2-hydroxyphenyl)sulfanylbutanoic acid Chemical compound OC(=O)CCCSC1=CC=CC=C1O KALOQPLSFUOZFB-UHFFFAOYSA-N 0.000 description 1
- DUVIDNZKBYILKO-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)sulfanylbutanoic acid Chemical compound OC(=O)CCCSC1=CC=C(Cl)C(Cl)=C1 DUVIDNZKBYILKO-UHFFFAOYSA-N 0.000 description 1
- DMFMSOSLFMWLHV-UHFFFAOYSA-N 4-(3-chlorophenyl)sulfanylbutanoic acid Chemical compound OC(=O)CCCSC1=CC=CC(Cl)=C1 DMFMSOSLFMWLHV-UHFFFAOYSA-N 0.000 description 1
- XCXPPNUEGDJRHT-UHFFFAOYSA-N 4-(3-hydroxyphenyl)sulfanylbutanoic acid Chemical compound OC(=O)CCCSC1=CC=CC(O)=C1 XCXPPNUEGDJRHT-UHFFFAOYSA-N 0.000 description 1
- PIYQKNNMKURSLU-UHFFFAOYSA-N 4-(3-methoxyphenyl)sulfanylbutanoic acid Chemical compound COC1=CC=CC(SCCCC(O)=O)=C1 PIYQKNNMKURSLU-UHFFFAOYSA-N 0.000 description 1
- SBRQBQHVYFSULX-UHFFFAOYSA-N 4-(4-chlorophenyl)sulfanylbutanoic acid Chemical compound OC(=O)CCCSC1=CC=C(Cl)C=C1 SBRQBQHVYFSULX-UHFFFAOYSA-N 0.000 description 1
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 1
- PPCGTVWKHISHFJ-UHFFFAOYSA-N 4-(phenylsulfanylmethyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CSC1=CC=CC=C1 PPCGTVWKHISHFJ-UHFFFAOYSA-N 0.000 description 1
- YFRJDWKQRDOWHG-UHFFFAOYSA-N 4-[(2-chlorophenyl)sulfanylmethyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CSC1=CC=CC=C1Cl YFRJDWKQRDOWHG-UHFFFAOYSA-N 0.000 description 1
- KDSOTNKRKZFNAV-UHFFFAOYSA-N 4-[(2-methoxyphenyl)sulfanylmethyl]benzoic acid Chemical compound COC1=CC=CC=C1SCC1=CC=C(C(O)=O)C=C1 KDSOTNKRKZFNAV-UHFFFAOYSA-N 0.000 description 1
- DANLZOIRUUHIIX-UHFFFAOYSA-N 4-[1-[2-chloro-6-(trifluoromethyl)benzoyl]indazol-3-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(C1=CC=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C(F)(F)F DANLZOIRUUHIIX-UHFFFAOYSA-N 0.000 description 1
- GRHQDJDRGZFIPO-UHFFFAOYSA-N 4-bromobutanoic acid Chemical compound OC(=O)CCCBr GRHQDJDRGZFIPO-UHFFFAOYSA-N 0.000 description 1
- QQCWOLFWEPZSBO-UHFFFAOYSA-N 5-(2-chlorophenyl)sulfanylpentanoic acid Chemical compound OC(=O)CCCCSC1=CC=CC=C1Cl QQCWOLFWEPZSBO-UHFFFAOYSA-N 0.000 description 1
- LWMJBUBGPPWDMB-UHFFFAOYSA-N 5-(2-methoxyphenyl)sulfanylpentanoic acid Chemical compound COC1=CC=CC=C1SCCCCC(O)=O LWMJBUBGPPWDMB-UHFFFAOYSA-N 0.000 description 1
- UJAMVFPVDSLLLN-UHFFFAOYSA-N 5-(3-chlorophenyl)sulfanylpentanoic acid Chemical compound OC(=O)CCCCSC1=CC=CC(Cl)=C1 UJAMVFPVDSLLLN-UHFFFAOYSA-N 0.000 description 1
- ZKWSBFJAFNNAKR-UHFFFAOYSA-N 5-(4-methoxyphenyl)sulfanylpentanoic acid Chemical compound COC1=CC=C(SCCCCC(O)=O)C=C1 ZKWSBFJAFNNAKR-UHFFFAOYSA-N 0.000 description 1
- BYHDDXPKOZIZRV-UHFFFAOYSA-N 5-phenylpentanoic acid Chemical compound OC(=O)CCCCC1=CC=CC=C1 BYHDDXPKOZIZRV-UHFFFAOYSA-N 0.000 description 1
- XUXQKZJUKDDKNF-UHFFFAOYSA-N 6-(2,5-dichlorophenyl)sulfanylhexanoic acid Chemical compound OC(=O)CCCCCSC1=CC(Cl)=CC=C1Cl XUXQKZJUKDDKNF-UHFFFAOYSA-N 0.000 description 1
- XHOBCIKOXCMCOC-UHFFFAOYSA-N 6-(2-acetylphenoxy)hexanoic acid Chemical compound CC(=O)C1=CC=CC=C1OCCCCCC(O)=O XHOBCIKOXCMCOC-UHFFFAOYSA-N 0.000 description 1
- IOVIFOJNYAMDLF-UHFFFAOYSA-N 6-(2-chlorophenyl)sulfanylhexanoic acid Chemical compound OC(=O)CCCCCSC1=CC=CC=C1Cl IOVIFOJNYAMDLF-UHFFFAOYSA-N 0.000 description 1
- KLJMLZBHWMSORJ-UHFFFAOYSA-N 6-(2-methoxyphenyl)sulfanylhexanoic acid Chemical compound COC1=CC=CC=C1SCCCCCC(O)=O KLJMLZBHWMSORJ-UHFFFAOYSA-N 0.000 description 1
- IBXORWIGQWPRNY-UHFFFAOYSA-N 6-(3,4-dichlorophenyl)sulfanylhexanoic acid Chemical compound OC(=O)CCCCCSC1=CC=C(Cl)C(Cl)=C1 IBXORWIGQWPRNY-UHFFFAOYSA-N 0.000 description 1
- NRXSBLAEUUHKIS-UHFFFAOYSA-N 6-(3-fluorophenyl)sulfanylhexanoic acid Chemical compound OC(=O)CCCCCSC1=CC=CC(F)=C1 NRXSBLAEUUHKIS-UHFFFAOYSA-N 0.000 description 1
- XGVBCLFZTVQOSU-UHFFFAOYSA-N 6-(3-methoxyphenyl)sulfanylhexanoic acid Chemical compound COC1=CC=CC(SCCCCCC(O)=O)=C1 XGVBCLFZTVQOSU-UHFFFAOYSA-N 0.000 description 1
- IMKWXJLOBKIPRC-UHFFFAOYSA-N 6-(4-fluorophenyl)sulfanylhexanoic acid Chemical compound OC(=O)CCCCCSC1=CC=C(F)C=C1 IMKWXJLOBKIPRC-UHFFFAOYSA-N 0.000 description 1
- AYDQSGIWKRVDFH-UHFFFAOYSA-N 6-(4-hydroxyphenyl)sulfanylhexanoic acid Chemical compound OC(=O)CCCCCSC1=CC=C(O)C=C1 AYDQSGIWKRVDFH-UHFFFAOYSA-N 0.000 description 1
- CSEJQDKFRRVFPS-UHFFFAOYSA-N 6-(4-methoxyphenyl)sulfanylhexanoic acid Chemical compound COC1=CC=C(SCCCCCC(O)=O)C=C1 CSEJQDKFRRVFPS-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- NVRVNSHHLPQGCU-UHFFFAOYSA-N 6-bromohexanoic acid Chemical compound OC(=O)CCCCCBr NVRVNSHHLPQGCU-UHFFFAOYSA-N 0.000 description 1
- HNQRYIHYPZDRJC-UHFFFAOYSA-N 8-(2-chlorophenyl)sulfanyloctanoic acid Chemical compound OC(=O)CCCCCCCSC1=CC=CC=C1Cl HNQRYIHYPZDRJC-UHFFFAOYSA-N 0.000 description 1
- JIEVEBIEXJWBAA-UHFFFAOYSA-N 8-(2-hydroxyphenyl)sulfanyloctanoic acid Chemical compound OC(=O)CCCCCCCSC1=CC=CC=C1O JIEVEBIEXJWBAA-UHFFFAOYSA-N 0.000 description 1
- HXWGFFNGNPBIEX-UHFFFAOYSA-N 8-(2-methoxyphenyl)sulfanyloctanoic acid Chemical compound COC1=CC=CC=C1SCCCCCCCC(O)=O HXWGFFNGNPBIEX-UHFFFAOYSA-N 0.000 description 1
- WKPVKFZTVBZPFU-UHFFFAOYSA-N 8-(3-methoxyphenyl)sulfanyloctanoic acid Chemical compound COC1=CC=CC(SCCCCCCCC(O)=O)=C1 WKPVKFZTVBZPFU-UHFFFAOYSA-N 0.000 description 1
- HTKKGMQHAVDRKZ-UHFFFAOYSA-N 8-(4-chlorophenyl)sulfanyloctanoic acid Chemical compound OC(=O)CCCCCCCSC1=CC=C(Cl)C=C1 HTKKGMQHAVDRKZ-UHFFFAOYSA-N 0.000 description 1
- OJSXICLEROKMBP-FFUDWAICSA-N 869705-22-6 Chemical compound C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(N)=O)C(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OJSXICLEROKMBP-FFUDWAICSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 1
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010007270 Carcinoid syndrome Diseases 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 208000025962 Crush injury Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- 206010012186 Delayed delivery Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- 208000008967 Enuresis Diseases 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010017865 Gastritis erosive Diseases 0.000 description 1
- 208000015872 Gaucher disease Diseases 0.000 description 1
- 101800001586 Ghrelin Proteins 0.000 description 1
- 241001460671 Glarea lozoyensis Species 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010062506 Heparin-induced thrombocytopenia Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019973 Herpes virus infection Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000028622 Immune thrombocytopenia Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000014429 Insulin-like growth factor Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 206010065973 Iron Overload Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241001502334 Mycobacterium avium complex bacterium Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102400000441 Obestatin Human genes 0.000 description 1
- 101800000590 Obestatin Proteins 0.000 description 1
- 206010031243 Osteogenesis imperfecta Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical compound CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000031951 Primary immunodeficiency Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100040918 Pro-glucagon Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 244000180577 Sambucus australis Species 0.000 description 1
- 235000018734 Sambucus australis Nutrition 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 208000016191 TSH-secreting pituitary adenoma Diseases 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 206010047627 Vitamin deficiencies Diseases 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- XJLATMLVMSFZBN-VYDXJSESSA-N actinonin Chemical compound CCCCC[C@H](CC(=O)NO)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1CO XJLATMLVMSFZBN-VYDXJSESSA-N 0.000 description 1
- XJLATMLVMSFZBN-UHFFFAOYSA-N actinonine Natural products CCCCCC(CC(=O)NO)C(=O)NC(C(C)C)C(=O)N1CCCC1CO XJLATMLVMSFZBN-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000570 acute poisoning Toxicity 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229920005603 alternating copolymer Polymers 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 210000004198 anterior pituitary gland Anatomy 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002686 anti-diuretic effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940124538 antidiuretic agent Drugs 0.000 description 1
- 239000003160 antidiuretic agent Substances 0.000 description 1
- 229940125684 antimigraine agent Drugs 0.000 description 1
- 239000002282 antimigraine agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 229960003796 atazanavir sulfate Drugs 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- PMDQGYMGQKTCSX-HQROKSDRSA-L calcium;[(2r,3s)-1-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3s)-oxolan-3-yl]oxycarbonylamino]-4-phenylbutan-2-yl] phosphate Chemical compound [Ca+2].C([C@@H]([C@H](OP([O-])([O-])=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 PMDQGYMGQKTCSX-HQROKSDRSA-L 0.000 description 1
- 229940080858 cancidas Drugs 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- JYIKNQVWKBUSNH-OGZDCFRISA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-OGZDCFRISA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000002281 colonystimulating effect Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 206010061811 demyelinating polyneuropathy Diseases 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- 229960002656 didanosine Drugs 0.000 description 1
- MUCZHBLJLSDCSD-UHFFFAOYSA-N diisopropyl fluorophosphate Chemical compound CC(C)OP(F)(=O)OC(C)C MUCZHBLJLSDCSD-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- ZZFKAZHZSSJSSE-UHFFFAOYSA-L disodium;[(cycloheptylamino)-[hydroxy(oxido)phosphoryl]methyl]-hydroxyphosphinate;hydrate Chemical compound O.[Na+].[Na+].OP(O)(=O)C(P([O-])([O-])=O)NC1CCCCCC1 ZZFKAZHZSSJSSE-UHFFFAOYSA-L 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- RIZMRRKBZQXFOY-UHFFFAOYSA-N ethion Chemical compound CCOP(=S)(OCC)SCSP(=S)(OCC)OCC RIZMRRKBZQXFOY-UHFFFAOYSA-N 0.000 description 1
- OOBFNDGMAGSNKA-UHFFFAOYSA-N ethyl 7-bromoheptanoate Chemical compound CCOC(=O)CCCCCCBr OOBFNDGMAGSNKA-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 108010015174 exendin 3 Proteins 0.000 description 1
- LMHMJYMCGJNXRS-IOPUOMRJSA-N exendin-3 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@H](C)O)[C@H](C)O)C(C)C)C1=CC=CC=C1 LMHMJYMCGJNXRS-IOPUOMRJSA-N 0.000 description 1
- 208000001936 exophthalmos Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 201000010103 fibrous dysplasia Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960005051 fluostigmine Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002933 fosamprenavir calcium Drugs 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940099052 fuzeon Drugs 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 208000037824 growth disorder Diseases 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 239000002835 hiv fusion inhibitor Substances 0.000 description 1
- 229940038661 humalog Drugs 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229940069330 human zinc insulin Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229950006971 incadronic acid Drugs 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 229960004243 indinavir sulfate Drugs 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 229940090438 infergen Drugs 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960002068 insulin lispro Drugs 0.000 description 1
- 108010010648 interferon alfacon-1 Proteins 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000009085 invasive aspergillosis Diseases 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000010438 iron metabolism Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 229960004184 ketamine hydrochloride Drugs 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960005230 nelfinavir mesylate Drugs 0.000 description 1
- NQHXCOAXSHGTIA-SKXNDZRYSA-N nelfinavir mesylate Chemical compound CS(O)(=O)=O.CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 NQHXCOAXSHGTIA-SKXNDZRYSA-N 0.000 description 1
- 229940071846 neulasta Drugs 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000005346 nocturnal enuresis Diseases 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 230000000624 ovulatory effect Effects 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 108010044644 pegfilgrastim Proteins 0.000 description 1
- 108010048732 pegylated erythropoietin Proteins 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- UGTYTOKVOXBJBZ-LINPMSLLSA-N peramivir hydrate Chemical compound O.O.O.O.CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N UGTYTOKVOXBJBZ-LINPMSLLSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 201000003067 thrombocytopenia due to platelet alloimmunization Diseases 0.000 description 1
- 229940019375 tiludronate Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Compounds and compositions for the delivery of active agents are provided . Methods of administration and preparation are also provided.
Description
ARYLSULFANYL COMPOUNDS AND COMPOSITIONS
FOR DELIVERING ACTIVE AGENTS
FIELD OF THE INVENTION
[1] The present invention relates to pharmaceutical compounds for delivering active agents, such as biologically or chemically active agents, to a target. Methods for the preparation and administration of such compositions are also disclosed.
BACKGROUND OF THE INVENTION
FOR DELIVERING ACTIVE AGENTS
FIELD OF THE INVENTION
[1] The present invention relates to pharmaceutical compounds for delivering active agents, such as biologically or chemically active agents, to a target. Methods for the preparation and administration of such compositions are also disclosed.
BACKGROUND OF THE INVENTION
[2] Conventional means for delivering active agents are often severely limited by biological, chemical and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, and/or the target itself Biologically and chemically active agents are particularly vulnerable to such barriers.
[3] In the delivery to animals of biologically active and chemically active pharmacological and therapeutic agents, barriers are imposed by the body.
Examples of physical barriers are the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain active agents but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.
Examples of physical barriers are the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain active agents but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.
[4] These barriers are of particular significance in the design of oral delivery systems.
Oral delivery of many biologically or chemically active agents would be the route of choice for SUBSTITUTE SHEET (RULE 26) ad.ministration to animals if not for biological, chemical, and physical barriers. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids;
antibiotics; and other organic substances. These agents may be rapidly rendered ineffective or destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, and the like. In addition, the size and structure of macromolecular drugs may prohibit absorption.
Oral delivery of many biologically or chemically active agents would be the route of choice for SUBSTITUTE SHEET (RULE 26) ad.ministration to animals if not for biological, chemical, and physical barriers. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids;
antibiotics; and other organic substances. These agents may be rapidly rendered ineffective or destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, and the like. In addition, the size and structure of macromolecular drugs may prohibit absorption.
[5] Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic fiypsin inhibitors, diisopropylfluorophosphate (DP'F) and trasylol) to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. However, broad spectrum use of such drug delivery systems is precluded because:
(1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.
(1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.
[6] Proteinoid microspheres have been used to deliver pharmaceuticals. See, for example, U.S. Patent Nos. 5,401,516; 5,443,841; and Re. 35,862. In addition, certain modified amino acids have been used to deliver pharmaceuticals. See, for example, U.S.
Patent Nos.
5,629,020; 5,643,957; 5,766,633; 5,776,888; and 5,866,536.
Patent Nos.
5,629,020; 5,643,957; 5,766,633; 5,776,888; and 5,866,536.
[7] More recently, a polymer has been conjugated to a modified amino acid or a derivative thereof via a linkage group to provide for polymeric delivery agents. The modified polymer may be any polymer, but preferred polymers include, but are not limited to, polyethylene glycol (PEG), and derivatives thereof. See, for example, lnternational Patent Publication No. WO 00/40203.
[8] However, there is still a need for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents by various routes.
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
[9] The present invention provides compounds and compositions which facilitate the delivery of active agents. Delivery agent compounds of the present invention include those having the formula:
Ri 0 \A OH
R4 Formula I
and pharnmaceutically acceptable salts thereof, wherein A is a branched or unbranched CI -C13 alkylene, C3-C13 arylene group, or a C3-C13 alkyl(arylene) group, Rl-R$ are independently a hydrogen, CI-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group.
Ri 0 \A OH
R4 Formula I
and pharnmaceutically acceptable salts thereof, wherein A is a branched or unbranched CI -C13 alkylene, C3-C13 arylene group, or a C3-C13 alkyl(arylene) group, Rl-R$ are independently a hydrogen, CI-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group.
[10] According to one embodiment, delivery agent compounds include those represented by Formula I above, in which A is a Ci-C12, or C, -Clo, or C1-C9, or Ci-Cg, or Cj-C7, or C2-C7, or C3-C7, or C4-C7 or C5-C7, or C6-C7 alkylene group; and/or at least one of Ra to R5 is a methyl, methoxy, hydroxy or halogen group (e.g., Cl or F).
[11] In a preferred embodiment, A, as defined above in Formula I, is an unsubstituted and unbranched, i.e. straight-chained, alkylene group.
[12] Mixtures of these delivery agent compounds may also be used.
[13] The invention also provides a pharmaceutical composition comprising at least one delivery agent compound of the present invention, and at least one active agent (e.g. a biologically active agent). When administered with an active agent, delivery agents of the present application improve the bioavailability of the active agent compared to administration of the active agent without the delivery agerit compound.
SUBSTITUTE SHEET (RULE 26) [14] Also provided is a dosage unit form comprising a pharmaceutical composition of the present invention. The dosage unit form may be in the form of a liquid or a solid, such as a tablet, capsule or particle, including a powder or sachet.
SUBSTITUTE SHEET (RULE 26) [14] Also provided is a dosage unit form comprising a pharmaceutical composition of the present invention. The dosage unit form may be in the form of a liquid or a solid, such as a tablet, capsule or particle, including a powder or sachet.
[15] Another embodiment is a method for adrn.inistering an active agent to an animal, particularly an animal in need of the active agent, by administering a pharmaceutical composition comprising at least one of delivery agent compound of the present invention and the active agent to the animal. Preferred routes of administration include the oral and intracolonic routes, particularly the oral route.
[16] Yet another embodiment of the present invention is a method of treating a disease or for achieving a desired physiological effect in an animal (e.g. a human) by administering to the animal the pharmaceutical composition of the present invention.
[17] Yet another embodiment of the present invention is a method of preparing a pharmaceutical composition of the present invention by mixing at least one delivery agent compound of the present invention, and at least one active agent.
[18] Yet another embodiment of the present invention is a method of increasing the bioavailability (e.g., the oral bioavailability) of a pharmaceutical composition containing an active agent (e.g., a biologically active agent) comprising adding a delivery agent compound of the present invention to the pharmaceutical composition.
I BRIEF DESCRIPTION OF THE DRAWINGS
I BRIEF DESCRIPTION OF THE DRAWINGS
[19] Figure 1 and 2 are graphs of aPTT times obtained after administration of heparin with delivery agents 1, 11, 35 and 59 to male rats over 90 minutes.
[20] Figure 3 is a graph of plasma heparin concentrations obtained after administration of heparin with delivery agents 2, 6 and 7 to male rats over 90 minutes.
[21] Figures 4 and 5 are graphs of serum rhGH levels in male rats after administration of rhGH with delivery agent 11 to male rats over 90 minutes.
[22] Figure 6 is a graph of serum LHRH concentrations after administration of LHRH
with delivery agents 5, 6, 7 and 58 to male rats over 30 minutes.
with delivery agents 5, 6, 7 and 58 to male rats over 30 minutes.
[23] Figure 7 is a graph of serum caspofungin acetate concentrations after administration of caspofungin acetate after administration of caspofungin acetate with delivery agent 14 over about 500 minutes SUBSTITUTE SHEET (RULE 26) DETAILED DESCRIPTION OF THE INVENTION
Definitions [24] The term "alkyl" refers to a straight-chained, branched, or substituted monovalent aliphatic hydrocarbon group containing no double or triple carbon-carbon bonds. Examples of alkyl group include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1-dimethylethyl (t-butyl).
Definitions [24] The term "alkyl" refers to a straight-chained, branched, or substituted monovalent aliphatic hydrocarbon group containing no double or triple carbon-carbon bonds. Examples of alkyl group include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1-dimethylethyl (t-butyl).
[25] The term "alkenyl" refers to a straight-chained, branched, or substituted monovalent aliphatic hydrocarbon group containing at least one carbon-carbon double bond.
Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl (al1y1), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2-butenyl.
Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl (al1y1), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2-butenyl.
[26] The term "'alkynyl" refers to a straight-chained, branched or substituted monovalent hydrocarbon group having at least one carbon-carbon triple bond.
Examples of alkynyl groups include, but are not limited to ethynyl, propynyl, and butnyl.
Examples of alkynyl groups include, but are not limited to ethynyl, propynyl, and butnyl.
[27] The term "alkylene" refers to a straight-chained, branched or substituted divalent aliphatic hydrocarbon group containing no double or triple bonds.
[28] The term "alkenylene" refers to a straight-chained, branched or substituted divalent aliphatic hydrocarbon group containing at least one carbon-carbon double bond.
[29] The term "alkynylene" refers to a straight-chained or branched divalent aliphatic hydrocarbon group containing at least one carbon-carbon triple bond.
[30] The term "alkyloxy" refers to an alkyl group attached via an oxygen linkage to the rest of the molecule. Examples of alkyloxy groups include, but are not limited to, -OCH3, and -OCZH5 groups.
[31] The term "aryl" refers to an monovalent aromatic group, i.e. a monovalent group having one or more unsaturated carbon rings. Examples of aryl groups, include, but are not limited to, phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
[32] The term arylene" refers to a divalent aromatic group, i.e. a divalent group having one or more unsaturated carbon rings.
[33] The term "alkyl(arylene)" refers to a divalent group containing an aromatic group with an alkyl group before andlor after the aromatic group.
SUBSTITUTE SHEET (RULE 26) [34] The term "aryloxy" refers to an aryl group attached via an oxygen linkage to the rest of the molecule, such as -OC6H5.
SUBSTITUTE SHEET (RULE 26) [34] The term "aryloxy" refers to an aryl group attached via an oxygen linkage to the rest of the molecule, such as -OC6H5.
[35] The term "insulin" includes recombinant forms of insulin (e.g.
recombinant human insulin), analogs of insulin lispro or Humalog~') as well as regular forms of insulin of human or other animal origin.
recombinant human insulin), analogs of insulin lispro or Humalog~') as well as regular forms of insulin of human or other animal origin.
[36] The term "heparin" includes unfractionated heparin, low molecular weight heparin, very low molecular weight heparin, of recombinant, human, or other animal origin.
[37] The term "LHRH" or "luteinizing hormone-releasing hormone" refers to a hormone produced by the hypothalamus that signals the anterior pituitary gland to begin secreting luteinizing hormone and follicle-stimulating hormone.
[38] The term "rhGH" refers to recombinant human growth hormone.
[39] The term "caspofungin" or "caspofungin acetate" refers to a water-soluble, semisynthetic lipopeptide derived from the fungus, Glarea lozoyensis, that has activity against Aspergilllus and Candida species. Caspofugin acetate (Cancidase) has been approved by the FDA and is indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other antifungal agents.
[40] Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents:
hydroxy, Ci-C4 alkyl, including methyl, ethyl, propyl, isopropyl, normal or iso- butyl; aryl, alkoxy, or aryloxy groups.
hydroxy, Ci-C4 alkyl, including methyl, ethyl, propyl, isopropyl, normal or iso- butyl; aryl, alkoxy, or aryloxy groups.
[41] The term "multiply interrupted" refers to between 2 and 10 interruptions in a chain where each interruption can be independently before, after, or between any other bond along the chain and may occur in any order or combination.
[42] The term "about" means generally means within 10%, preferably within 5%, and more preferably within 1% of a given range.
[43] The term "short stature" refers to a subject with a size (e.g. a height) that is significantly below what is considered normal. Growth hormone, e.g., human growth hormone, is indicated for short stature.
Delivery Agent Compounds [44] Delivery agent compounds of the present invention include those compounds represented by Formula I below, and phannaceutically acceptable sales thereof:
SUBSTITUTE SHEET (RULE 26) R, O
~A O H
I
R4 Formula I
wherein [45] A is a branched or unbranched CI-C13 alkylene, C3-C13 arylene group, or a alkyl(arylene) group, [46] Rl-R5 are independently a hydrogen, Cl-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group.
Delivery Agent Compounds [44] Delivery agent compounds of the present invention include those compounds represented by Formula I below, and phannaceutically acceptable sales thereof:
SUBSTITUTE SHEET (RULE 26) R, O
~A O H
I
R4 Formula I
wherein [45] A is a branched or unbranched CI-C13 alkylene, C3-C13 arylene group, or a alkyl(arylene) group, [46] Rl-R5 are independently a hydrogen, Cl-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group.
[47] In one embodiment delivery agents of the present invention include those compounds represented by Formula I above, wherein A is a Cl-C9 alkylene group, a C2-C9 alkylene group, a C3-C9 alkylene group, a C4-C9 alkylene group, a C5-C9 alkylene group, a C6-C9 alkylene group, a C 7-C9 alkylene group, a Cg-Cg alkylene group, a C2-Cg alkylene group, a C3-C8 alkylene group, a C4-C8 alkylene group, a C5-Cg alkylene group, a C6-C8 alkylene group, a C7-C8 alkylene group, a C3-C7 alkylene group, a C4-C7 alkylene group, a C5-C7 alkylene group, a C6-C7 alkylene group, a C; alkylene group, a Cg alkylene group, or a Cg alkylene group.
[48] In another embodiment delivery agents of the present invention include those compounds represented by Formula I above, wherein A is selected from:
or SUBSTITUTE SHEET (RULE 26) [49] In another embodiment of the present invention, delivery agent compounds of the present invention include those compounds represented by Formula I above in which at least one of RI-R5 is a methyl, methoxy, hydroxy or halogen group. In a preferred embodiment, delivery agent compounds include those in which A is defined as in the preceding paragraph and at least one of R1-R5 is a methyl, methoxy, hydroxy or halogen group.
or SUBSTITUTE SHEET (RULE 26) [49] In another embodiment of the present invention, delivery agent compounds of the present invention include those compounds represented by Formula I above in which at least one of RI-R5 is a methyl, methoxy, hydroxy or halogen group. In a preferred embodiment, delivery agent compounds include those in which A is defined as in the preceding paragraph and at least one of R1-R5 is a methyl, methoxy, hydroxy or halogen group.
[50] In one embodiment of the present invention, delivery agent compounds are selected from Formula I above, in which at least one of RI-R5 is a methyl group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of RI-R5 is a methoxy group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of Rl-R5 is a hydroxy group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of Ri-RS is a halogen, preferably at least one of Rl-R5 is a chlorine atom or at least one of Ri-R5 is a fluorine atom.
[51] In one embodiment of the present invention, 3, 4 - diehlorophenylsulfanyl acetic acid is excluded as a delivery agent of Formula I. However, in various embodiments 3, 4 -dichlorophenylsulfanyl acetic acid may be included in compositions that further include an active agent (e.g., a biologically active agent).
[52] In one embodiment of the present invention, delivery agent compounds include those represented by Formula II below, and pharmaceutically acceptable salts thereof R, 0 I n OH
R4 Formula Il wherein [53] n- 1 to 9, and R,-R5 are independently hydrogen, CI-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy with the proviso that when n = 1, R2 and R3 are not both chlorine.
SUBSTITUTE SHEET (RULE 26) [54] In one embodiment of the present invention, delivery agent compounds include compounds represented by Formula II above, in which n is 1, 2, 3, 4, 5, 6, 7, 8 or 9.
Alternatively, nmaybe 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, 8-9, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3 or 1-2.
R4 Formula Il wherein [53] n- 1 to 9, and R,-R5 are independently hydrogen, CI-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy with the proviso that when n = 1, R2 and R3 are not both chlorine.
SUBSTITUTE SHEET (RULE 26) [54] In one embodiment of the present invention, delivery agent compounds include compounds represented by Formula II above, in which n is 1, 2, 3, 4, 5, 6, 7, 8 or 9.
Alternatively, nmaybe 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, 8-9, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3 or 1-2.
[55] In another embodiment of the present invention, delivery agent compounds include compounds represented by Formula II above, in which at least one of R, -R5 is a methyl, methoxy, hydroxy or halogen group. In one embodiment of the present invention, delivery agent compounds are selected from Formula II above, in which at least one of Rl-R5 is a methyl group.
In another embodiment, delivery agent compounds are selected from Formula lI
above in which at least one ofRl-R5 is a methoxy group. In another embodiment, delivery agent compounds are selected from Formula II above in which at least one of RI-R5 is a hydroxy group. In another embodiment, delivery agent compounds are selected from Forrnula II above in which at least one of R, -R5 is a balogen, preferably at least one of RI-RS is a chlorine atom or at least one of Rl-R5 is a fluorine atom.
In another embodiment, delivery agent compounds are selected from Formula lI
above in which at least one ofRl-R5 is a methoxy group. In another embodiment, delivery agent compounds are selected from Formula II above in which at least one of RI-R5 is a hydroxy group. In another embodiment, delivery agent compounds are selected from Forrnula II above in which at least one of R, -R5 is a balogen, preferably at least one of RI-RS is a chlorine atom or at least one of Rl-R5 is a fluorine atom.
[56] In one embodiment of the present invention, 3, 4 - dichlorophenylsulfanyl acetic acid is excluded as a delivery agent of Formula II.
[57] The delivery agent compounds may be in the forin of the free base or pharmaceutically acceptable salts thereof, such as pharmaceutically acceptable acid addition salts. Suitable salts include, but are not limited to, organic and inorganic salts, for exaznple ammonium, acetate salt, citrate salt, halide (preferably hydrochloride), hydroxide, sulfate, nitrate, phosphate, alkoxy, perchlorate, tetrafluoroborate, carboxylate, mesylate, fumerate, malonate, succinate, tartrate, acetate, gluconate, and maleate. Preferred salts include, but are not limited to, citrate and mesylate salts. The salts may also be solvates, including ethanol solvates, and hydrates.
[58] Salts of the delivery agent compounds of the present invention may be prepared by methods known in the art. For example, citrate salts and mesylate salts may be prepared in ethanol, toluene and citric acid.
[59] The delivery agent compound may be purified by recrystallization or by fractionation on one or more solid chromatographic supports, alone or linked in tandem.
Suitable recrystallization solvent systems include, but are not limited to, ethanol, water, heptane, SUBSTITUTE SHEET (RULE 26) ethyl acetate, acetonitrile, acetone, methanol, and tetrahydrofuran (THF) and mixtures thereof.
Fractionation may be performed on a suitable chromatographic support such as aluinina, using methanol/n-propanol mixtures as the mobile phase; reverse phase chromatography using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water or an appropriate buffer as the mobile phase. When anion exchange chromatography is performcd, preferably a 0-500 mM sodium chloride gradient is employed.
Suitable recrystallization solvent systems include, but are not limited to, ethanol, water, heptane, SUBSTITUTE SHEET (RULE 26) ethyl acetate, acetonitrile, acetone, methanol, and tetrahydrofuran (THF) and mixtures thereof.
Fractionation may be performed on a suitable chromatographic support such as aluinina, using methanol/n-propanol mixtures as the mobile phase; reverse phase chromatography using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water or an appropriate buffer as the mobile phase. When anion exchange chromatography is performcd, preferably a 0-500 mM sodium chloride gradient is employed.
[60] The delivery agent may contain a polymer conjugated to it by a linkage group selected from the group consisting of -NHC(0)NH-, -C(O)NH-,-NHC(0)-; -OOC-, -COO-, -NHC(0)0-, -OC(O)NH-, -CH2NH -NHCH2-, -CH2NHC(O)O-, -OC(0)NHCHZ-,-CH2NHCOCH2O-, -OCH2C(0)NHCH2-, - NHC(0)CH2O-, -OCHZC(O)NH-, -NH-, -0-, and carbon-carbon bond, with the proviso that the polymeric delivery agent is not a polypeptide or polyamino acid. The polymer may be any polymer including, but not limited to, alternating copolymers, block copolymers and random copolymers, which are safe for use in mammals.
Preferred polymers include, but are not limited to, polyethylene;
polyacrylates;
polymethacrylates; poly(oxyethylene); poly(propylene); polypropylene glycol;
polyethylene glycol (PEG); and derivatives thereof and combinations thereof. The molecular weight of the polymer typically ranges from about 100 to about 200,000 daltons. The molecular weight of the polymer preferably ranges from about 200 to about 10,000 daltons. In one embodiment, the molecular weight of the polymer ranges from about 200 to about 600 daltons and more preferably ranges from about 300 to about 550 daltons.
Preferred polymers include, but are not limited to, polyethylene;
polyacrylates;
polymethacrylates; poly(oxyethylene); poly(propylene); polypropylene glycol;
polyethylene glycol (PEG); and derivatives thereof and combinations thereof. The molecular weight of the polymer typically ranges from about 100 to about 200,000 daltons. The molecular weight of the polymer preferably ranges from about 200 to about 10,000 daltons. In one embodiment, the molecular weight of the polymer ranges from about 200 to about 600 daltons and more preferably ranges from about 300 to about 550 daltons.
[61] Non-limiting examples of delivery agent compounds of formula I include those shown below and pharmaceutically acceptable salts thereof:
\ S OH
8-(2-Methoxy-phenylsulfanyl)-octanoic acid Compound I
SUBSTITUTE SHEET (RULE 26) OH
8-(2,5-Dimethyl-phenylsulfanyE)-octanoic acid Compound 2 "",~OH
6-(2-Methoxy-phenylsulfanyl)-hexanoic acid Compound 3 (LSJOH
10-(2-Methoxy-phenylsulfanyl)-decanoic acid Compound 4 &SOH
8-(2-Hydroxy-phenylsulfanyl)-octanoic acid Compound 5 SUBSTITUTE SHEET (RULE 26) S OH
6-(2,5-Dimethyl-phenylsulfanyl)-hexanoic acid Compound 6 S OH
4-(2,5-Dimethyl-phenylsuifanyl)-hutyric acid Coinpound 7 OH O
S ~OH
10-(2-Hydroxy-phenylsulfanyl)-decanoic acid Compound 8 ~ s oH
~
3-(2,5-Dimethyl-phenylsuIfanyl)-.propionic acid Compound 9 SUBSTITUTE SHEET (RULE 26) OH
8-(4-Methoxy-phenylsulfanyl)-octanoic acid Compound 10 O
H
Z O
HO
8-(4-Hydroxy-phenylsulfanyl)-octanoic acid Compound 11 &SOH
4-(2-Hydroxy-phenylsulfanyl)-butyric acid Compound 12 oH
(4-Methoxy-phenylsulfanyl)-acetic acid Compound 13 ~ S OH
5-(4-Methoxy-phenylsulfanyl)-pentanoic acid Compound 14 SUBSTITUTE SHEET (RULE 26) O
S oH
o C
6-(4-Methoxy-phenylsulfanyl)-hexanoic acid Compound 15 ~ S OH
7-(2-Methoxy-phenyisulfanyl)-heptanoic acid Compound 16 S OH
O 74-(4-Methoxy-phenyisulfanyl)-butyric acid Compound 17 ~ S~OH
3-(4-Methoxy-phenyisulfanyl)-propionic acid Compound 18 SUBSTITUTE SHEET (RULE 26) Q
~ S 01"I
5-(2-Methoxy-phenylsulfanyl)-pentanoic acid Compound 19 10-(3-Methoxy-phenylsulfanyl)-decanoic acid Compound 20 O
S
OH
6-(3-Methoxy-phenylsulfanyl)-hexanoic acid Compound 21 ~O ~ S QH
/
8-(3-Methoxy-phenylsulfanyl)-octanoic acid Compound 22 CI S"IAOH
(3-Chloro-phenylsulfanyl)-acetic acid SUBSTITUTE SHEET (RULE 26) Compound 23 CI \ s oH
o 5-(3-Chloro-phenylsulfanyl)-pentanoic acid Compound 24 CI
S OH
5-(2-Chloro-phenylsulfanyl)-pentanoic acid Compound 25 \ ~ OH
6-(2-Chloro-phenylsulfanyl)-hexanoic acid Compound 26 O
o s OH
/
4-(3-Methoxy-phenylsulfanyl)-butyric acid Compound 27 SUBSTITUTE SHEET (RULE 26) ci 0 &SOH
(2-Chloro-phenylsulfanyl)-acetic acid Compound 28 O
CI S OH
~ /
4-(3-Chloro-phenylsulfanyl)-butyric acid Compound 29 cl o S oH
8-(2-Chloro-phenylsulfanyl)-octanoic acid Compound 30 CI Q
S OH
4-(2-Chloro-phenylsulfanyl)-butyric acid Compound 31 CI S OH
6-(3-Chloro-phenyisulfanyl)-hexanoic acid Compound 32 SUBSTITUTE SHEET (RULE 26) S OH
a Cl 8-(4-Chloro-phenylsulfanyl)-octanoic acid Compound 33 GI ~ S OH
( /
4-(4-Chloro-phenylsulfanyl)-butyric acid Compound 34 O
I::: S OH
HO
6-(4-Hydroxy-phenylsulfanyl)-hexanoic acid Compound 35 HO S OH
/
4-(3-Hydroxy-phenylsulfanyl)-butyric acid Compound 36 HO OH
$-(3-Hydroxy-phenyisulfanyl)-octanoic acid SUBSTITUTE SHEET (RULE 26) Compound 37 S ~OH
HO J:: 10-(4-Hydroxy-phenylsulfanyl)-decanoic acid Compound 38 HO ~ S OH
10-(3-Hyd roxy-phenylsulfanyl)-decanoic acid Compound 39 Sv /
CI
(2,5-Dichloro-phenylsulfanyl)-acetic acid Compound 40 S OH
CI
6-(2,5-Dichloro-phenylsulfanyl)-hexanoic acid Compound 41 SUBSTITUTE SHEET (RULE 26) :s0H
l 3,4-Dichloro-phenylsulfanyl)-acefiic acid Compound 42 ci ~ S 0 ~ `
CI
6-(3,4-Dichloro-phenylsulfanyl)-hexanoic acid Compound 43 Cl ~ S~OH
O
3-(2-Chloro-phenylsulfanyl)-propionic acid Compound 44 CI S~OH
3-(3-Chloro-phenylsulfanyl)-propionic acid Compound 45 HO ~ S~
OH
/
(3-Hydroxy-phenylsulfanyl)-acetic acid Compound 46 SUBSTITUTE SHEET (RULE 26) S\~
OH
(2-Fluoro-phenylsulfanyl)-acetic acid Compound 47 ~ S OH
6-(2-Fluoro-phenylsuffanyl)-hexanoic acid Compound 48 OH
6-(3-Fluoro-phenylsulfanyl)-hexanoic acid Compound 49 cl 0 S OH
CI
4-(2,5-Dichloro-phenyfsulfanyl)-butyric acid Compound 50 O
F S\~
OH
(3-Fluoro-phenylsulfanyl)-acetic acid SUBSTITUTE SHEET (RULE 26) Compound 51 F ~ S
~ OH
/
4-(3-Fluoro-phenylsulfanyl)-butyric acid Compound 52 CI ~ S
OH
/
CI
4-(3,4-Dichloro-phenylsulfanyl)-butyric acid Compound 53 S
OH
4-(2-Fluoro-phenylsulfanyl)wbutyric acid Compound 54 S
I ~ OH
/
F
(4-Fluoro-phenylsulfanyl)-acetic acid Compound 55 SUBSTITUTE SHEET (RULE 26) ~ S
F OH
~ ~
4-(4-Fluoro-phenylsulfanyl)-butyric acid Compound 56 S ",,~OH
F
6-(4-Fluoro-phenylsulfanyl)-hexanoic acid Compound 57 OH
(2,5-Dimethyl)-acetic acid Compound 58 CI OH
4-(2-Chloro-phenylsulfanylmethyl)-benzoic acid Compound 59 SUBSTITUTE SHEET (RULE 26) OH
[4-(2-Methoxy-phenylsulfanylmethyl)-phenyl] -acetic acid Compound 60 p/ 0H
S
4-(2-Methoxy-phenylsulfanylmethyl)-benzoic acid Compound 61 OH
(4-1'henylsulfanylmethyl-phenyl)-acetic acid Compound 62 SUBSTITUTE SHEET (RULE 26) O
~ OH
S
4-Phenylsulfanylmethyl-benzoic acid Compound 63 OH
S
CI
4-(4-Chloro-phenylsulfanylmethyl)-benzoic acid Compound 64 OH OH
` S \
4-(2-Hydroxy-phenylsulfanylmethyl)-benzoic acid Compound 65 SUBSTITUTE SHEET (RULE 26) OH
OH
ry [4-(2-Hydroxy-phenylsulfanyhnethyl)-phenyl]-acetic acid Compound 66 Active Agents [62] Active agents suitable for use in the present invention include biologically active agents and chemically active agents, including, but not limited to, pesticides, pharrnacological agents, and therapeutic agents. Suitable active agents include those that are rendered less effective, ineffective or are destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes and the like. Also included as suitable active agents are those macromolecular agents whose physiochemical characteristics, such as, size, structure or charge, prohibit or impede absorption when dosed orally.
\ S OH
8-(2-Methoxy-phenylsulfanyl)-octanoic acid Compound I
SUBSTITUTE SHEET (RULE 26) OH
8-(2,5-Dimethyl-phenylsulfanyE)-octanoic acid Compound 2 "",~OH
6-(2-Methoxy-phenylsulfanyl)-hexanoic acid Compound 3 (LSJOH
10-(2-Methoxy-phenylsulfanyl)-decanoic acid Compound 4 &SOH
8-(2-Hydroxy-phenylsulfanyl)-octanoic acid Compound 5 SUBSTITUTE SHEET (RULE 26) S OH
6-(2,5-Dimethyl-phenylsulfanyl)-hexanoic acid Compound 6 S OH
4-(2,5-Dimethyl-phenylsuifanyl)-hutyric acid Coinpound 7 OH O
S ~OH
10-(2-Hydroxy-phenylsulfanyl)-decanoic acid Compound 8 ~ s oH
~
3-(2,5-Dimethyl-phenylsuIfanyl)-.propionic acid Compound 9 SUBSTITUTE SHEET (RULE 26) OH
8-(4-Methoxy-phenylsulfanyl)-octanoic acid Compound 10 O
H
Z O
HO
8-(4-Hydroxy-phenylsulfanyl)-octanoic acid Compound 11 &SOH
4-(2-Hydroxy-phenylsulfanyl)-butyric acid Compound 12 oH
(4-Methoxy-phenylsulfanyl)-acetic acid Compound 13 ~ S OH
5-(4-Methoxy-phenylsulfanyl)-pentanoic acid Compound 14 SUBSTITUTE SHEET (RULE 26) O
S oH
o C
6-(4-Methoxy-phenylsulfanyl)-hexanoic acid Compound 15 ~ S OH
7-(2-Methoxy-phenyisulfanyl)-heptanoic acid Compound 16 S OH
O 74-(4-Methoxy-phenyisulfanyl)-butyric acid Compound 17 ~ S~OH
3-(4-Methoxy-phenyisulfanyl)-propionic acid Compound 18 SUBSTITUTE SHEET (RULE 26) Q
~ S 01"I
5-(2-Methoxy-phenylsulfanyl)-pentanoic acid Compound 19 10-(3-Methoxy-phenylsulfanyl)-decanoic acid Compound 20 O
S
OH
6-(3-Methoxy-phenylsulfanyl)-hexanoic acid Compound 21 ~O ~ S QH
/
8-(3-Methoxy-phenylsulfanyl)-octanoic acid Compound 22 CI S"IAOH
(3-Chloro-phenylsulfanyl)-acetic acid SUBSTITUTE SHEET (RULE 26) Compound 23 CI \ s oH
o 5-(3-Chloro-phenylsulfanyl)-pentanoic acid Compound 24 CI
S OH
5-(2-Chloro-phenylsulfanyl)-pentanoic acid Compound 25 \ ~ OH
6-(2-Chloro-phenylsulfanyl)-hexanoic acid Compound 26 O
o s OH
/
4-(3-Methoxy-phenylsulfanyl)-butyric acid Compound 27 SUBSTITUTE SHEET (RULE 26) ci 0 &SOH
(2-Chloro-phenylsulfanyl)-acetic acid Compound 28 O
CI S OH
~ /
4-(3-Chloro-phenylsulfanyl)-butyric acid Compound 29 cl o S oH
8-(2-Chloro-phenylsulfanyl)-octanoic acid Compound 30 CI Q
S OH
4-(2-Chloro-phenylsulfanyl)-butyric acid Compound 31 CI S OH
6-(3-Chloro-phenyisulfanyl)-hexanoic acid Compound 32 SUBSTITUTE SHEET (RULE 26) S OH
a Cl 8-(4-Chloro-phenylsulfanyl)-octanoic acid Compound 33 GI ~ S OH
( /
4-(4-Chloro-phenylsulfanyl)-butyric acid Compound 34 O
I::: S OH
HO
6-(4-Hydroxy-phenylsulfanyl)-hexanoic acid Compound 35 HO S OH
/
4-(3-Hydroxy-phenylsulfanyl)-butyric acid Compound 36 HO OH
$-(3-Hydroxy-phenyisulfanyl)-octanoic acid SUBSTITUTE SHEET (RULE 26) Compound 37 S ~OH
HO J:: 10-(4-Hydroxy-phenylsulfanyl)-decanoic acid Compound 38 HO ~ S OH
10-(3-Hyd roxy-phenylsulfanyl)-decanoic acid Compound 39 Sv /
CI
(2,5-Dichloro-phenylsulfanyl)-acetic acid Compound 40 S OH
CI
6-(2,5-Dichloro-phenylsulfanyl)-hexanoic acid Compound 41 SUBSTITUTE SHEET (RULE 26) :s0H
l 3,4-Dichloro-phenylsulfanyl)-acefiic acid Compound 42 ci ~ S 0 ~ `
CI
6-(3,4-Dichloro-phenylsulfanyl)-hexanoic acid Compound 43 Cl ~ S~OH
O
3-(2-Chloro-phenylsulfanyl)-propionic acid Compound 44 CI S~OH
3-(3-Chloro-phenylsulfanyl)-propionic acid Compound 45 HO ~ S~
OH
/
(3-Hydroxy-phenylsulfanyl)-acetic acid Compound 46 SUBSTITUTE SHEET (RULE 26) S\~
OH
(2-Fluoro-phenylsulfanyl)-acetic acid Compound 47 ~ S OH
6-(2-Fluoro-phenylsuffanyl)-hexanoic acid Compound 48 OH
6-(3-Fluoro-phenylsulfanyl)-hexanoic acid Compound 49 cl 0 S OH
CI
4-(2,5-Dichloro-phenyfsulfanyl)-butyric acid Compound 50 O
F S\~
OH
(3-Fluoro-phenylsulfanyl)-acetic acid SUBSTITUTE SHEET (RULE 26) Compound 51 F ~ S
~ OH
/
4-(3-Fluoro-phenylsulfanyl)-butyric acid Compound 52 CI ~ S
OH
/
CI
4-(3,4-Dichloro-phenylsulfanyl)-butyric acid Compound 53 S
OH
4-(2-Fluoro-phenylsulfanyl)wbutyric acid Compound 54 S
I ~ OH
/
F
(4-Fluoro-phenylsulfanyl)-acetic acid Compound 55 SUBSTITUTE SHEET (RULE 26) ~ S
F OH
~ ~
4-(4-Fluoro-phenylsulfanyl)-butyric acid Compound 56 S ",,~OH
F
6-(4-Fluoro-phenylsulfanyl)-hexanoic acid Compound 57 OH
(2,5-Dimethyl)-acetic acid Compound 58 CI OH
4-(2-Chloro-phenylsulfanylmethyl)-benzoic acid Compound 59 SUBSTITUTE SHEET (RULE 26) OH
[4-(2-Methoxy-phenylsulfanylmethyl)-phenyl] -acetic acid Compound 60 p/ 0H
S
4-(2-Methoxy-phenylsulfanylmethyl)-benzoic acid Compound 61 OH
(4-1'henylsulfanylmethyl-phenyl)-acetic acid Compound 62 SUBSTITUTE SHEET (RULE 26) O
~ OH
S
4-Phenylsulfanylmethyl-benzoic acid Compound 63 OH
S
CI
4-(4-Chloro-phenylsulfanylmethyl)-benzoic acid Compound 64 OH OH
` S \
4-(2-Hydroxy-phenylsulfanylmethyl)-benzoic acid Compound 65 SUBSTITUTE SHEET (RULE 26) OH
OH
ry [4-(2-Hydroxy-phenylsulfanyhnethyl)-phenyl]-acetic acid Compound 66 Active Agents [62] Active agents suitable for use in the present invention include biologically active agents and chemically active agents, including, but not limited to, pesticides, pharrnacological agents, and therapeutic agents. Suitable active agents include those that are rendered less effective, ineffective or are destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes and the like. Also included as suitable active agents are those macromolecular agents whose physiochemical characteristics, such as, size, structure or charge, prohibit or impede absorption when dosed orally.
[63] For example, biologically or chemically active agents suitable for use in the present invention include, but are not limited to, proteins; polypeptides;
peptides; hormones;
polysaccharides, and particularly mixtures of muco-polysaccharides;
carbohydrates; lipids; small polar organic molecules (i.e. polar organic molecules having a molecular weight of 500 daltons or less); other organic compounds; and particularly compounds which by themselves do not pass (or which pass only a fraction of the administered dose) through the gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro-intestinal tract; or any combination thereof.
peptides; hormones;
polysaccharides, and particularly mixtures of muco-polysaccharides;
carbohydrates; lipids; small polar organic molecules (i.e. polar organic molecules having a molecular weight of 500 daltons or less); other organic compounds; and particularly compounds which by themselves do not pass (or which pass only a fraction of the administered dose) through the gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro-intestinal tract; or any combination thereof.
[64] Further examples include, but are not limited to, the following, including synthetic, natural or recombinant sources thereof: growth hormones, including human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, and porcine growth hozxnones; growth hormone releasing hormones; growth hormone releasing factor, interferons, including a-interferon (e.g., interferon alfaconml (available as Infergen from SUBSTITUTE SHEET (RULE 26) InterMune, Inc. of Brisbane, CA)), (3-interferon and y-interferon; interleukin-1; interleukin-2;
insulin, including porcine, bovine, human, and human recombinant, optionally having counter ions including zinc, sodium, calcium and ammonium; insulin-like growth factor, including IGF-1; heparin, including unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin and ultra low molecular weight heparin; calcitonin, including salmon, eel, porcine and human; erythropoietin;
atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; protease inhibitors;
adrenocorticotropin, gonadotropin releasing hormone; oxytocin; leutinizing-hormone-releasing-hormone; follicle stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim;
prostaglandins;
cyclosporin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate);
vancomycin;
desferrioxamine (DFO); bisphosphonates, including alendronate, tiludronate, etidronate, clodronate, pamidronate, olpadronate, and incadronate; parathyroid hormone (PTH), including its fragments; anti-migraine agents such as sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, BIBN-4096BS and other calcitonin gene-related proteins antagonists;
glucagon-like peptide 1(GLP-1); Argatroban; glucagon; antimicrobials, including antibiotics, anti-bacterials and anti-fungal agents; vitamins; analogs, fragments, mimetics or polyethylene glycol (PEG)-modified derivatives of these compounds; or any combination thereof. Non-limiting examples of antibiotics include gram-positive acting, bacteriocidal, lipopeptidal and cyclic peptidal antibiotics, such as daptomycin and analogs thereof.
Delivery systems [65] The pharnaceutical composition of the present invention comprises one or more delivery agent compounds of the present invention, and one or more active agents (e.g., biologically active agents). In one embodiment, one or more of the delivery agent compounds, or salts of these compounds, may be used as a delivery agent by mixing delivery agent compounds with the active agent prior to administration to form an administration composition.
insulin, including porcine, bovine, human, and human recombinant, optionally having counter ions including zinc, sodium, calcium and ammonium; insulin-like growth factor, including IGF-1; heparin, including unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin and ultra low molecular weight heparin; calcitonin, including salmon, eel, porcine and human; erythropoietin;
atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; protease inhibitors;
adrenocorticotropin, gonadotropin releasing hormone; oxytocin; leutinizing-hormone-releasing-hormone; follicle stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim;
prostaglandins;
cyclosporin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate);
vancomycin;
desferrioxamine (DFO); bisphosphonates, including alendronate, tiludronate, etidronate, clodronate, pamidronate, olpadronate, and incadronate; parathyroid hormone (PTH), including its fragments; anti-migraine agents such as sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, BIBN-4096BS and other calcitonin gene-related proteins antagonists;
glucagon-like peptide 1(GLP-1); Argatroban; glucagon; antimicrobials, including antibiotics, anti-bacterials and anti-fungal agents; vitamins; analogs, fragments, mimetics or polyethylene glycol (PEG)-modified derivatives of these compounds; or any combination thereof. Non-limiting examples of antibiotics include gram-positive acting, bacteriocidal, lipopeptidal and cyclic peptidal antibiotics, such as daptomycin and analogs thereof.
Delivery systems [65] The pharnaceutical composition of the present invention comprises one or more delivery agent compounds of the present invention, and one or more active agents (e.g., biologically active agents). In one embodiment, one or more of the delivery agent compounds, or salts of these compounds, may be used as a delivery agent by mixing delivery agent compounds with the active agent prior to administration to form an administration composition.
[66] The administration compositions may be in the form of a liquid. The solution medium may be water (for example, for salmon calcitonin, parathyroid hormone, and erythropoietin), 25% aqueous propylene glycol (for example, for heparin) and phosphate buffer (for example, for rhGH). Other dosing vehicles include polyethylene glycol.
Dosing solutions SUBSTITUTE SHEET (RULE 26) may be prepared by mixing a solution of the delivery agent compound with a solution of the active agent, just prior to administration. Alternately, a solution of the delivery agent compound (or active agent) may be mixed with the solid form of the active agent (or delivery agent compound). The delivery agent compound and the active agent may also be mixed as dry powders. The delivery agent compound and the active agent can also be admixed during the manufacturing process. Alternatively, the delivery agent compound and active agent can be separately administered in sequential fashion.
Dosing solutions SUBSTITUTE SHEET (RULE 26) may be prepared by mixing a solution of the delivery agent compound with a solution of the active agent, just prior to administration. Alternately, a solution of the delivery agent compound (or active agent) may be mixed with the solid form of the active agent (or delivery agent compound). The delivery agent compound and the active agent may also be mixed as dry powders. The delivery agent compound and the active agent can also be admixed during the manufacturing process. Alternatively, the delivery agent compound and active agent can be separately administered in sequential fashion.
[67] The dosing solutions may optionally contain additives such as phosphate buffer salts, citric acid, glycols, or other dispersing agents. Stabilizing additives may be incorporated into the solution, preferably at a concentration ranging between about 0.1 and 20% (wlv).
[68] The administration compositions may alternately be in the form of a solid, such as a tablet, capsule or particle, such as a powder or sachet. Solid dosage forms may be prepared by mixing the solid form of the compound with the solid form of the active agent.
Alternately, a solid may be obtained from a solution of compound and active agent by methods known in the art, such as freeze-drying (lyophilization), precipitation, crystallization and solid dispersion.
Alternately, a solid may be obtained from a solution of compound and active agent by methods known in the art, such as freeze-drying (lyophilization), precipitation, crystallization and solid dispersion.
[69] The administration compositions of the present invention may also include one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives therreof. Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitors.
[70] The amount of active agent used in an administration composition of the present invention is an amount effective to accomplish the purpose of the particular active agent for the target indication. The amount of active agent in the compositions typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount can be less than that amount when the composition is used in a dosage unit form because the dosage unit form may contain a plurality of delivery agent compound/active agent compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount. The total effective amount can then be administered in cumulative units containing, in total, an effective amount of the active agent.
[71] Generally, the amount of delivery agent compound in the composition is an amount effective to facilitate delivery of the active agent. The total amount of active agent and SUBSTITUTE SHEET (RULE 26) delivery agent to be used can be determined by methods known to those skilled in the art.
However, because the compositions of the invention may deliver active agents more efficiently than compositions containing the active agent alone, lower amounts of biologically or chemically active agents than those used in prior dosage unit forins or delivery systems can be administered to the subject, while still achieving the same blood levels and/or therapeutic effects. Generally, the weight ratio of delivery agent to active agent ranges from about 1000:1 or 800:1 to about 10:1 or 1:10, and preferably ranges from about 400:1 or 200:1 to about 100:1 or 25:1. Other ranges are contemplated to be within acceptable ranges for delivery of some active compounds, such as from about 100;1 or 50:1 to about 5:1 or 2.5:1, or from about 60:1 or 30;1 to about 1:1 or 0.5:1. Such ranges and ratios can be determined by one skilled in the art.
However, because the compositions of the invention may deliver active agents more efficiently than compositions containing the active agent alone, lower amounts of biologically or chemically active agents than those used in prior dosage unit forins or delivery systems can be administered to the subject, while still achieving the same blood levels and/or therapeutic effects. Generally, the weight ratio of delivery agent to active agent ranges from about 1000:1 or 800:1 to about 10:1 or 1:10, and preferably ranges from about 400:1 or 200:1 to about 100:1 or 25:1. Other ranges are contemplated to be within acceptable ranges for delivery of some active compounds, such as from about 100;1 or 50:1 to about 5:1 or 2.5:1, or from about 60:1 or 30;1 to about 1:1 or 0.5:1. Such ranges and ratios can be determined by one skilled in the art.
[72] The presently disclosed delivery agent compounds facilitate the delivery of biologically and chemically active agents, particularly in oral, intranasal, sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous, intramuscular and ocular systems, as well as traversing the blood-brain barrier.
[73] Dosage unit forms can also include any one or combination of excipients, diluents, disintegrants, lubricants, plasticizers, colorants, flavorants, taste-masking agents, sugars, sweeteners, salts, and dosing vehicles, including, but not limited to, water, 1,2-propane diol, ethanol, olive oil, or any combination thereof.
[74] The compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals, including but not limited to birds such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.
[75] The system is particularly advantageous for delivering chemically or biologically active agents that would otherwise be destroyed or rendered less effective by conditions encountered before the active agent reaches its target zone (i.e. the area in which the active agent of the delivery composition is to be released) and within the body of the animal to which they are administered. Particularly, the compounds and compositions of the present invention are useful for orally administering active agents, especially those that are not ordinarily orally deliverable, or those for which improved delivery is desired.
SUBSTITUTE SHEET (RULE 26) [76] The compositions comprising the compounds and active agents have utility in the delivery of active agents to selected biological systems and in an increased or improved bioavailability of the active agent compared to administration of the active agent without the delivery agent. Delivery can be improved by delivering more active agent over a period of time, or in delivering the active agent in a particular time period (such as to effect quicker or delayed delivery), or in delivering the active agent at a specific time, or over a period of time (such as sustained delivery).
SUBSTITUTE SHEET (RULE 26) [76] The compositions comprising the compounds and active agents have utility in the delivery of active agents to selected biological systems and in an increased or improved bioavailability of the active agent compared to administration of the active agent without the delivery agent. Delivery can be improved by delivering more active agent over a period of time, or in delivering the active agent in a particular time period (such as to effect quicker or delayed delivery), or in delivering the active agent at a specific time, or over a period of time (such as sustained delivery).
[77] Another embodiment of the present invention is a method for the treatment or prevention of a disease or for achieving a desired physiological effect, such as any one of the diseases or conditions listed in the table below, in an animal by administering the composition of the present invention. Preferably, an effective amount of the composition for the treatment or prevention of the desired disease or for achieving the desired physiological effect is administered. Specific indications for active agents can be found in the The Physicians ' Desk Reference (58th Ed., 2004, Medical Economics Company, Inc., Montvale, NJ), and Fauci, AS, et.
al., Harrison's Principles of Inteznal Medicine (14th Ed., 1998, McGraw-Hill Health Professions Division, New York. Both of these references are herein incorporated by reference in their entirety. The active agents in the table below include their analogs, fragments, rnimeties, and polyethylene glycol-modified derivatives (e.g., the PEGylated derivative of granulocyte colony stimulating factor sold as Neulasta ).
SUBSTITUTE SHEET (RULE 26) Active Agent Disease and Physiological Effect Growth hormones (including human recombinant Growth disorders growth hormone and growth-hormone releasing factors and its analogs) Interferons, including a, P and y Viral infection, including chronic cancer, hepatitis, and multiple sclerosis Interleukins (e.g. Interleukin-1; interleukin-2) Viral infection; cancer; cell mediated immunity; and transplant rejection;
Insulin; Insulin-like growth factor IGF-1 Diabetes Immune Globulins, such as IVIg smallpox, rabies, and diphtheria, Alzheimer's Disease; Primary immunodeficiencies; Acute Guillain-Barre syndrome; Chronic idiopatllic demyelinating polyneuropathy (CIDP); Myasthenia gravis, polymyositis, and dermatomyositis; neonatal immune thrombocytopenia, heparin-induced thrombocytopenia, and antiphospholipid antibody syndrome: Posttransftision purpura.
Heparin Treatment and Prevention of Thrombosis, including (Deep Vein Thrombosis); prevention of blood coagulation Calcitonin Osteoporosis; diseases of the bone; bone pain;
analgesic (including pain associated with osteoporosis or cancer) Erythropoietin, Pegylated erythropoietin. Anemia; HIV/HIV-therapy Associated Anemia;
Chemotherapeutically-Induced Anemia Atrial naturetic factor Vasodilation Antigens Infection CPHPC Reduction of amyloid deposits and systemic amyloidoisis often (but not always) in connection with Alzheimer's disease,Type II diabetes, and other amyloid-based diseases Monoclonal antibodies To prevent graft rejection; cancer; used in assays to detect diseases Somatostatinloctreotide Bleeding ulcer; erosive gastritis; variceal bleeding;
diarrhea; acromegaly; TSH-secreting pituitary adenomas; secretory pancreatic tumors; carcinoid syndrome; reduce proptosis/ thyroid-associated ophthalmopathy; reduce macular edema/retinopathy Protease inhibitors HIV Infection/AIDS
Adrenocorticotropin High cholesterol (to lower cholesterol) Gonadotropin releasing hormone Ovulatory disfunction (to stimulate ovulation) Oxytocin Labor disfunction (to stimulate contractions) Leutinizing-hormone-releasing-hormone; Regulate reproductive function Leutinizing Hormone; follicle stimulating hormone Glucocerebrosidase Gaucher disease (to metabolize lipoprotein) SUBSTITUTE SHEET (RULE 26) Active Agerit Disease and PhysiologicalEffect Thrombopoietin Thrombocytopenia Filgrastim (Granulocyte Colony Stimulating shorten the duration of chemotherapy-induced Factor); GM-CSF, (sargramostim) and their neutropenia and thus treat or prevent infection in Pegylated forms chemotherapy patients; Inhibit the growth of or to kill Mycobacterium Intracellular Avium Infection (MAC) RNAi Huntington, Alzheimers, Viral Infections (HIV, Hepatitis A, B or C, RSV), Cancers; Macular Degeneration Prostaglandins Hypertension Cyclosporin Transplant rejection; psoriasis, inflammatory alopecias; Sjogren's syndrome; Keratoconjunctivitis Sicca Vasopressin Nocturnal Enuresis; antidiuretic Cromolyn sodium; Asthma; allergies Vancomycin Treat or prevent antimicrobial-induced infections including, but not limitted to methacillin-resistant Staphalococcus aureus and Staph.
epidermiditis gallium salts (such as gallium nitrate) Osteoporosis; Paget's disease;
Inhibits osteoclasts;
Promotes osteoblastic activity, hypercalcemia, including cancer related hypercalcemia, urethral (urinary tract) malignancies; anti-tumors, cancers, including urethral and bladder cancers; lymphoma;
malignancies (including bladder cancer); leukemia;
management of bone metastases (and associated pain); muliple myelo:ma, attenuate inunune response, including allogenic transplant rejections; disrupt iron metabolism; promote cell migration; wound repair;
to attenuate or treat infectious processes of mycobacterium species, including but not limited to mycobacteriurn rubercolosis, and mycobacterium avium complex Desferrioxamine (DFO) Iron overload Parathyroid hormone (PTH), including its Osteoporosis;
fragments. Diseases of the bone Antiinicrobials Infection including but not limited to gram-positive bacterial infection Vitamins Treat and prevent Vitamin deficiencies SUBSTITUTE SHEET (RULE 26) Active Agent Disease andPhysioingical Effect Bisphosphonates Osteoporosis; Paget's disease; bone tumors and metastases (and associated pain); Breast cancer;
including as adjuvant therapy for early stage breast cancer; management of bone metastases (and associated pain), including bone metastases associate with breast cancer, prostate cancer, and lung cancer;
Inhibits osteoclasts; Promotes osteoblastic activity;
treat and/or prevent bone mineral density (bmd) loss;
multiple myeloma; prevention of bone complications related to malignant osteolysis; fibrous dysplasia;
pediatric osteogenesis imperfecta; hypercalcemia, urethral (urinary tract) malignancies; reflex sympathetic dystropy synodrome, acute back pain after vertebral crush fracture, chronic inflammatory joint disease, renal bone disease, extrosseous calcifications, analgesic, vitamin D intoxication, periarticular ossifications BIBN4096BS -(1-Piperidinecarboxamide. N-[2-[ [ Anti-migraine; calcitonin gene-related peptide 5-amino-l-[ [4-(4-pyridinyl)-1- antagonist piperazinyl)carbonyl]pentyl]amino]-l -[ (3,5-dibromo-4-hydroxyphenyl)methyl] -2-oxoethyl] -4(1,4-dihydro-2 -oxo-3 (2kIQ-quinazolinyl)-. [R-(R*,S*)]-) Glucagon improving glycemic control (e.g. treating hypoglycemia and controlling hypoglycemic reactions), obesity; a diagnostic aid in the radiogical examination of the stomach, duodenum, small bowel and colon; Treat acute poisoning With Cardiovascular Agents including, but not limited to, calcium channel blockers, beta blockers GLP-1, Exendin - 3, Exendin - 4, Obestatin Diabetes; improving glyceniic control (e.g. treating hypoglycemia and controlling hypoglycemic reactions), obesity dipeptidyl peptidase TV (DPP-4) inhibitors Diabetes; improving glycemic control (e.g, treating hypoglycemia), obesity acyclovir Used to treat herpes infections of the skin, lip and genitals; herpes zoster (shingles); and chickenpox HIV Entry Inhibitors (e.g. Fuzeon) Inhibit entry of HIV into host cells Sumatriptin, almotriptan, naratriptan, rizatriptan, anti-migraine serotonin agonists frovatriptan and eletriptan (piperidinyloxy)phenyl, (piperidinyloxy)pyridinyl, (piperidinylsulfanyl)phenyl and (piperidinylsulfanyl)pyridinyl compounds SUBSTITUTE SHEET (RULE 26) Active Agent Disease and Physiologic.aY lffect Neuraminidase inhibitors: peramivir, zanamivir, Antivirals oseltamivir, BCX-1898, BCX-1827, BCX-1989, BCX 1923, BCX 1827 and A315675; M2 inhibitors: amantadine, rimantadine;
NucleosidelNucleotide Reverse Transcriptase Inhibitors, Non-nucleoside Reverse Transcriptase Inhibitors, Protease hihibitors, Fusion inhibitors:
thiovir, thiophosphonoformate, foscarnet, enfuviritide, zidovudine, didanosine, zalcitabine, stavudine, lan-iivudine, emtricitabine, abacavir, azidothymidine, tenofovir disoproxil, delavridine, efavirenz, nevirapine, ritonavir, nelfinavir mesylate, saquinvir mesylate, indinavir sulfate, amprenavir, lopinavir, lopinavir, fosamprenavir calcium, atazanavir sulfate Peptide YY (PYY) and PYY-like Peptides (e.g. Obesity, Diabetes, Eating Disorders, Insulin-PYY[3-36]) Resistance Syndromes [78] For example, one embodiment of the present invention is a method for treating a patient suffering from or susceptible to diabetes by administering insulin and at least one of the delivery agent compounds of the present invention.
al., Harrison's Principles of Inteznal Medicine (14th Ed., 1998, McGraw-Hill Health Professions Division, New York. Both of these references are herein incorporated by reference in their entirety. The active agents in the table below include their analogs, fragments, rnimeties, and polyethylene glycol-modified derivatives (e.g., the PEGylated derivative of granulocyte colony stimulating factor sold as Neulasta ).
SUBSTITUTE SHEET (RULE 26) Active Agent Disease and Physiological Effect Growth hormones (including human recombinant Growth disorders growth hormone and growth-hormone releasing factors and its analogs) Interferons, including a, P and y Viral infection, including chronic cancer, hepatitis, and multiple sclerosis Interleukins (e.g. Interleukin-1; interleukin-2) Viral infection; cancer; cell mediated immunity; and transplant rejection;
Insulin; Insulin-like growth factor IGF-1 Diabetes Immune Globulins, such as IVIg smallpox, rabies, and diphtheria, Alzheimer's Disease; Primary immunodeficiencies; Acute Guillain-Barre syndrome; Chronic idiopatllic demyelinating polyneuropathy (CIDP); Myasthenia gravis, polymyositis, and dermatomyositis; neonatal immune thrombocytopenia, heparin-induced thrombocytopenia, and antiphospholipid antibody syndrome: Posttransftision purpura.
Heparin Treatment and Prevention of Thrombosis, including (Deep Vein Thrombosis); prevention of blood coagulation Calcitonin Osteoporosis; diseases of the bone; bone pain;
analgesic (including pain associated with osteoporosis or cancer) Erythropoietin, Pegylated erythropoietin. Anemia; HIV/HIV-therapy Associated Anemia;
Chemotherapeutically-Induced Anemia Atrial naturetic factor Vasodilation Antigens Infection CPHPC Reduction of amyloid deposits and systemic amyloidoisis often (but not always) in connection with Alzheimer's disease,Type II diabetes, and other amyloid-based diseases Monoclonal antibodies To prevent graft rejection; cancer; used in assays to detect diseases Somatostatinloctreotide Bleeding ulcer; erosive gastritis; variceal bleeding;
diarrhea; acromegaly; TSH-secreting pituitary adenomas; secretory pancreatic tumors; carcinoid syndrome; reduce proptosis/ thyroid-associated ophthalmopathy; reduce macular edema/retinopathy Protease inhibitors HIV Infection/AIDS
Adrenocorticotropin High cholesterol (to lower cholesterol) Gonadotropin releasing hormone Ovulatory disfunction (to stimulate ovulation) Oxytocin Labor disfunction (to stimulate contractions) Leutinizing-hormone-releasing-hormone; Regulate reproductive function Leutinizing Hormone; follicle stimulating hormone Glucocerebrosidase Gaucher disease (to metabolize lipoprotein) SUBSTITUTE SHEET (RULE 26) Active Agerit Disease and PhysiologicalEffect Thrombopoietin Thrombocytopenia Filgrastim (Granulocyte Colony Stimulating shorten the duration of chemotherapy-induced Factor); GM-CSF, (sargramostim) and their neutropenia and thus treat or prevent infection in Pegylated forms chemotherapy patients; Inhibit the growth of or to kill Mycobacterium Intracellular Avium Infection (MAC) RNAi Huntington, Alzheimers, Viral Infections (HIV, Hepatitis A, B or C, RSV), Cancers; Macular Degeneration Prostaglandins Hypertension Cyclosporin Transplant rejection; psoriasis, inflammatory alopecias; Sjogren's syndrome; Keratoconjunctivitis Sicca Vasopressin Nocturnal Enuresis; antidiuretic Cromolyn sodium; Asthma; allergies Vancomycin Treat or prevent antimicrobial-induced infections including, but not limitted to methacillin-resistant Staphalococcus aureus and Staph.
epidermiditis gallium salts (such as gallium nitrate) Osteoporosis; Paget's disease;
Inhibits osteoclasts;
Promotes osteoblastic activity, hypercalcemia, including cancer related hypercalcemia, urethral (urinary tract) malignancies; anti-tumors, cancers, including urethral and bladder cancers; lymphoma;
malignancies (including bladder cancer); leukemia;
management of bone metastases (and associated pain); muliple myelo:ma, attenuate inunune response, including allogenic transplant rejections; disrupt iron metabolism; promote cell migration; wound repair;
to attenuate or treat infectious processes of mycobacterium species, including but not limited to mycobacteriurn rubercolosis, and mycobacterium avium complex Desferrioxamine (DFO) Iron overload Parathyroid hormone (PTH), including its Osteoporosis;
fragments. Diseases of the bone Antiinicrobials Infection including but not limited to gram-positive bacterial infection Vitamins Treat and prevent Vitamin deficiencies SUBSTITUTE SHEET (RULE 26) Active Agent Disease andPhysioingical Effect Bisphosphonates Osteoporosis; Paget's disease; bone tumors and metastases (and associated pain); Breast cancer;
including as adjuvant therapy for early stage breast cancer; management of bone metastases (and associated pain), including bone metastases associate with breast cancer, prostate cancer, and lung cancer;
Inhibits osteoclasts; Promotes osteoblastic activity;
treat and/or prevent bone mineral density (bmd) loss;
multiple myeloma; prevention of bone complications related to malignant osteolysis; fibrous dysplasia;
pediatric osteogenesis imperfecta; hypercalcemia, urethral (urinary tract) malignancies; reflex sympathetic dystropy synodrome, acute back pain after vertebral crush fracture, chronic inflammatory joint disease, renal bone disease, extrosseous calcifications, analgesic, vitamin D intoxication, periarticular ossifications BIBN4096BS -(1-Piperidinecarboxamide. N-[2-[ [ Anti-migraine; calcitonin gene-related peptide 5-amino-l-[ [4-(4-pyridinyl)-1- antagonist piperazinyl)carbonyl]pentyl]amino]-l -[ (3,5-dibromo-4-hydroxyphenyl)methyl] -2-oxoethyl] -4(1,4-dihydro-2 -oxo-3 (2kIQ-quinazolinyl)-. [R-(R*,S*)]-) Glucagon improving glycemic control (e.g. treating hypoglycemia and controlling hypoglycemic reactions), obesity; a diagnostic aid in the radiogical examination of the stomach, duodenum, small bowel and colon; Treat acute poisoning With Cardiovascular Agents including, but not limited to, calcium channel blockers, beta blockers GLP-1, Exendin - 3, Exendin - 4, Obestatin Diabetes; improving glyceniic control (e.g. treating hypoglycemia and controlling hypoglycemic reactions), obesity dipeptidyl peptidase TV (DPP-4) inhibitors Diabetes; improving glycemic control (e.g, treating hypoglycemia), obesity acyclovir Used to treat herpes infections of the skin, lip and genitals; herpes zoster (shingles); and chickenpox HIV Entry Inhibitors (e.g. Fuzeon) Inhibit entry of HIV into host cells Sumatriptin, almotriptan, naratriptan, rizatriptan, anti-migraine serotonin agonists frovatriptan and eletriptan (piperidinyloxy)phenyl, (piperidinyloxy)pyridinyl, (piperidinylsulfanyl)phenyl and (piperidinylsulfanyl)pyridinyl compounds SUBSTITUTE SHEET (RULE 26) Active Agent Disease and Physiologic.aY lffect Neuraminidase inhibitors: peramivir, zanamivir, Antivirals oseltamivir, BCX-1898, BCX-1827, BCX-1989, BCX 1923, BCX 1827 and A315675; M2 inhibitors: amantadine, rimantadine;
NucleosidelNucleotide Reverse Transcriptase Inhibitors, Non-nucleoside Reverse Transcriptase Inhibitors, Protease hihibitors, Fusion inhibitors:
thiovir, thiophosphonoformate, foscarnet, enfuviritide, zidovudine, didanosine, zalcitabine, stavudine, lan-iivudine, emtricitabine, abacavir, azidothymidine, tenofovir disoproxil, delavridine, efavirenz, nevirapine, ritonavir, nelfinavir mesylate, saquinvir mesylate, indinavir sulfate, amprenavir, lopinavir, lopinavir, fosamprenavir calcium, atazanavir sulfate Peptide YY (PYY) and PYY-like Peptides (e.g. Obesity, Diabetes, Eating Disorders, Insulin-PYY[3-36]) Resistance Syndromes [78] For example, one embodiment of the present invention is a method for treating a patient suffering from or susceptible to diabetes by administering insulin and at least one of the delivery agent compounds of the present invention.
[79] Following administration, the active agent present in the composition or dosage unit form is taken up into the circulation. The bioavailability of the agent can be readily assessed by measuring a known pharmacological activity in blood, e.g. an increase in blood clotting time caused by heparin, or a decrease in circulating calcium levels caused by calcitonin.
Alternatively, the circulating levels of the active agent itself can be measured directly.
Alternatively, the circulating levels of the active agent itself can be measured directly.
[80] One embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of insulin and an effective amount of at least one of the delivery agents described herein. For example, one embodiment of the present invention provides a pharmaceutical composition comprising about 50 to 800 mg/kg (e.g. 200 mg/kg) of insulin and about 0.1 to 2.0 mg/kg (e.g. 0.5mg/kg) of any one of the delivery agent compounds of the present invention.
[81] Yet another embodiment is method of treating diseases characterized by hyperglycemia, such as diabetes, comprising administering a pharmaceutical composition of the present invention to a subject.
SUBSTITUTE SHEET (RULE 26) [82] One embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of heparin and an effective amount of at least one of the delivery agents described herein. For example, one embodiment of the present invention provides a pharmaceutical composition comprising about 5 to 125 mg/kg (e.g. 25 mg/kg or 80 mg/kg) of heparin and about 5 to 500 mg/kg (e.g. 50 mg/kg or 200 mg/kg) of any one of the delivery agent compounds of the present invention.
SUBSTITUTE SHEET (RULE 26) [82] One embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of heparin and an effective amount of at least one of the delivery agents described herein. For example, one embodiment of the present invention provides a pharmaceutical composition comprising about 5 to 125 mg/kg (e.g. 25 mg/kg or 80 mg/kg) of heparin and about 5 to 500 mg/kg (e.g. 50 mg/kg or 200 mg/kg) of any one of the delivery agent compounds of the present invention.
[83] Yet another embodiment is method of treating or preventing disease characterized by intravascular thrombi by administering an effective amount of heparin and an effective amount of a delivery agent of the present invention to a subject.
[84] Yet another embodiment is method of preventing DVT in susceptible individuals by administering an effective amount of heparin and an effective amount of a delivery agent compound of the present invention to a subject.
[85] One embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of rhGH and an effcctive amount of at least one of the delivery agents described herein. For example, one embodiment of the present invention provides a pharmaceutical composition comprising about 0.25 to 10 mg/kg (e.g. 3 mg/kg) of rhGH and about 50 to 500 mg/kg (e.g. 200 mg/kg) of any one of the delivery agent compounds of the present invention.
[86] Yet another embodiment is method of treating or preventing short stature by administering an effective amount of rhGH and an effective amount of at least one delivery agent compound of the present invention to a subj ect.
[87] Yet another embodiment is method of treating or preventing a disease which requires supplementation of growth hormone by administering an effective amount of at least one delivery agent compound of the present invention to a subject.
[88] One embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of LHRH and an effective amount of at least one of the delivery agents described herein. For example, one embodiment of the present invention provides a pharmaceutical composition comprising about 0.1 to 10 mg/kg (e.g. 1 mg/kg) of LHRH and about 50 - 500 mg/kg (e.g. 200 mg/kg) of any one of the delivery agent compounds of the present invention.
SUBSTITUTE SHEET (RULE 26) [89] Yet another embodiment is method of treating or preventing infertility in men or women which requires supplementation of LHRH by administering an effective amount of LHRH and an effective amount of at least one delivery agent of the present invention to a subj ect.
SUBSTITUTE SHEET (RULE 26) [89] Yet another embodiment is method of treating or preventing infertility in men or women which requires supplementation of LHRH by administering an effective amount of LHRH and an effective amount of at least one delivery agent of the present invention to a subj ect.
[90] Yet another embodiment is method of treating or preventing a disease which requires supplementation of LHRH by administering an effective amount of LHRH
and an effective amount of at least one delivery agent of the present invention to a subject.
and an effective amount of at least one delivery agent of the present invention to a subject.
[91] One embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of caspofungin acetate (e.g. Cancidas ) and an effective amount of at least one of the delivery agents described herein. For example, one embodiment of the present invention provides a pharmaceutical composition comprising about 5 to 125 mg/kg (e.g.
25 mglkg) of caspofungin acetate and about 50 to 500 mg/kg (e.g. 200 mg/kg) of any one of the delivery agent compounds of the present invention.
25 mglkg) of caspofungin acetate and about 50 to 500 mg/kg (e.g. 200 mg/kg) of any one of the delivery agent compounds of the present invention.
[92] Yet another embodiment is method of treating or preventing candidiasis or other systemic or localized fungal infections by administering an effective amount of caspofungin acetate and an effective amount of a delivery agent of the present invention to the subject.
EXANTPLES
EXANTPLES
[93] The following examples illustrate the present invention without limitation.
Example 1 -- Preparation of 8- 2-Methox - hen lsnlfan 1-octanoic acid (Compound ]:
Example 1 -- Preparation of 8- 2-Methox - hen lsnlfan 1-octanoic acid (Compound ]:
[94] To a 250 mL flask, equipped with a magnetic stir bar, was added ethyl 8-bromo-octanoate (13.8 mL, 66 mmol), 2-methoxybenzenethiol (8.0 mL, 66 mmol), and 80 mL ethyl alcohol. The reaction vessel was cooled with an extemal ice bath while potassium hydroxide (5.2g 93 mmol) was added. The reaction was allowed to warm to room temperature and stirred 16 hours under a nitrogen atmosphere. The white precipitate was removed by suction filtration and solvent removed under reduced pressure. The concentrate was then dissolved in 10 mL ethyl alcohol, treated with 90 mL of aqueous 1 N sodium hydroxide solution and heated for 1 hour at reflux. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C. The product (16.2 g, 87%) was isolated by filtration as an off-white powder, mp 62-63 C.
SUBSTITUTE SHEET (RULE 26) Found: C: 63.79 %, H: 7.91 % S: 11.25 %; C15H2203S requires C: 63.80 %,H: 7.85 %, S: 11.35 %; 1H NMR (d6-DMSO): S 7.21, d, IH (aryl H); 8 7.15 td, 1H (aryl H); $ 6.96, d, 1H (aryl H);
6 6.92 td, 1H (aryl H); S 3.8, s, 3H (OCH3); 8 2.85, t, 2H (CH2 a to S); 6 2.2, t, 2H (CH2 a to COOH); S 1.6-1.2, multiplet, 10H (rest of CH2`s).
Example 2 -- Preparation of S- 2 5-Dimeth l- hen lsulfan 1-octanoic acid (Compound 2):
SUBSTITUTE SHEET (RULE 26) Found: C: 63.79 %, H: 7.91 % S: 11.25 %; C15H2203S requires C: 63.80 %,H: 7.85 %, S: 11.35 %; 1H NMR (d6-DMSO): S 7.21, d, IH (aryl H); 8 7.15 td, 1H (aryl H); $ 6.96, d, 1H (aryl H);
6 6.92 td, 1H (aryl H); S 3.8, s, 3H (OCH3); 8 2.85, t, 2H (CH2 a to S); 6 2.2, t, 2H (CH2 a to COOH); S 1.6-1.2, multiplet, 10H (rest of CH2`s).
Example 2 -- Preparation of S- 2 5-Dimeth l- hen lsulfan 1-octanoic acid (Compound 2):
[95] To a 500 mL flask, equipped with a magnetic stir bar, was added ethyl 8-bromo-octanoate (10.8 mL, 52 mmol), 2,5-dimethylbenzenethiol (7.0 mL, 52 mmol), and 72 mL ethyl alcohol. The reaction vessel was cooled with an external ice bath while potassium hydroxide (4.45 g, 79 mmol) was added. The reaction was allowed to warm to room temperature and stirred 16 hours under a nitrogen atmosphere. A second amount of potassium hydroxide (2.0 g, 36 mmol) was added with 130 mL
of ethyl alcohol. The reaction was allowed to stir at room temperature for 18 hours. To the reaction mixture was added 50 mL of aqueous I N sodium hydroxide solution and was heated for 1 hour at reflux. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C. The product (13.9 g, 96%) was isolated by filtration as an off-white powder, mp 60-63 C. Found: C: 68.69 %, H: 8.82 /a S: 11.26 %; C16H2402S requires C.
68.53 %, H: 8.63 %, S: 11.43 %; 1H NMR (d6-DMSO): 612.0, broad s, 1H (COOH); 6 7.07, s, 1H (aryl H); S 7.06, d, 1H (aryl H); 6 6.88, d, 1H (aryl H); 6 2.90, t, 2H (CH2 a to S); S 2.25, s, 3H (aryl-CH3); 8 2.21, s, 3H (Ary1-CH3); 6 2.19, t, 2H (CH2 a to COOH); 6 1.6-1.2, multiplet, lOH
(rest of CH2's).
Exam le 3-- Pre aration of 6- 2-Methox - hen `lsutlfan l-hexanoic acid Com ound 3):
of ethyl alcohol. The reaction was allowed to stir at room temperature for 18 hours. To the reaction mixture was added 50 mL of aqueous I N sodium hydroxide solution and was heated for 1 hour at reflux. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C. The product (13.9 g, 96%) was isolated by filtration as an off-white powder, mp 60-63 C. Found: C: 68.69 %, H: 8.82 /a S: 11.26 %; C16H2402S requires C.
68.53 %, H: 8.63 %, S: 11.43 %; 1H NMR (d6-DMSO): 612.0, broad s, 1H (COOH); 6 7.07, s, 1H (aryl H); S 7.06, d, 1H (aryl H); 6 6.88, d, 1H (aryl H); 6 2.90, t, 2H (CH2 a to S); S 2.25, s, 3H (aryl-CH3); 8 2.21, s, 3H (Ary1-CH3); 6 2.19, t, 2H (CH2 a to COOH); 6 1.6-1.2, multiplet, lOH
(rest of CH2's).
Exam le 3-- Pre aration of 6- 2-Methox - hen `lsutlfan l-hexanoic acid Com ound 3):
[96] To a 500 mL flask, equipped with a magnetic stir bar, was added ethyl 6-bromo-hexanoate (12.0 mL, 67 mmol), 2-methoxybenzenethiol (8.2 mL, 67 mmol), and 52 mL ethyl alcohol. The reaction vessel was cooled with an external ice bath while potassium hydroxide (7.72 g, 138 mmol) was added. The reaction was allowed to stir at room temperature for 18 hours under nitrogen atmosphere. Water (100 mL) and 50 mL of aqueous 1 N
sodium hydroxide solution were added and the mixture allowed to stir at room temperature for 18 hours. Ethyl alcohol was distilled at atmospheric pressure. The resulting solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours. The product (163 g, 95%) was isolated by filtration as an off white powder, mp 81-82 C. Found: C: 60.70 %, H: 7.08 % S:
SUBSTITUTE SHEET (RULE 26) 12,46 %; C13H1803S requires C: 60.87 %, H: 7.17 %, S: 12.50 %; 1H NMR (d6-DMSO): 512.0, broad s, 1H (COOH); S 7.20, dd, 1H (aryl H); 6 7.16, dt, 1H (aryl H); 6 6.96, dd, IH (aryl H); 8 6.93, dt, 1H (aryl H); 6 3.80, s, 3H (OCH3); 6 2.86, t, 2H (CH2 a to S); &
2.20, t, 2H (CH2 a to COOH); 6 1.6-1.3, multiplet, 6H (rest ofCH2`s).
Example 4 -- Preparation of 10- 2-Methox - hen lsulfan 1-decanoic acid (Compound 4:
sodium hydroxide solution were added and the mixture allowed to stir at room temperature for 18 hours. Ethyl alcohol was distilled at atmospheric pressure. The resulting solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours. The product (163 g, 95%) was isolated by filtration as an off white powder, mp 81-82 C. Found: C: 60.70 %, H: 7.08 % S:
SUBSTITUTE SHEET (RULE 26) 12,46 %; C13H1803S requires C: 60.87 %, H: 7.17 %, S: 12.50 %; 1H NMR (d6-DMSO): 512.0, broad s, 1H (COOH); S 7.20, dd, 1H (aryl H); 6 7.16, dt, 1H (aryl H); 6 6.96, dd, IH (aryl H); 8 6.93, dt, 1H (aryl H); 6 3.80, s, 3H (OCH3); 6 2.86, t, 2H (CH2 a to S); &
2.20, t, 2H (CH2 a to COOH); 6 1.6-1.3, multiplet, 6H (rest ofCH2`s).
Example 4 -- Preparation of 10- 2-Methox - hen lsulfan 1-decanoic acid (Compound 4:
[97] Prepared analogously to Compound 3 with ethyl 10-bromo-decanoate (11.47 g, 41.1 mmol), 2-methoxybenzenethiol (5.0 mL, 41.1 mmol), 40 mL ethyl alcohol, and potassium hydroxide (7.00 g, 124.8 mmol). The product (12.3 g, 96%) was isolated by filtration as an off-white powder, mp 65-66 C. Found: C: 65.71 %, H: 8.38 % S: 10.25 %; C17H2603S
requires C:
65.77 %, H: 8.44 %, S: 10.33 /Q; 1H NMR (d6-DMSO): 812.0, broad s, 1H (COOH);
S 7.20, dd, 1 H (aryl H); 6 7.16, dt, 1 H (aryl H); S 6.96, dd, 1 H(aryl H); 8 6.93, dt, 1 H (aryl H); S 3.80, s, 3H
(OCH3); S 2.85, t, 2H (CH2 a to S); 6 2.18, t, 2H (CH2 a to COOH); 6 1.6-1.2, multiplet, 14H
(rest of CHZ`s).
Example 5 -- Preparation of 8- 2-H drox - hen lsulfan 1-octan.oic acid Com ound 5):
requires C:
65.77 %, H: 8.44 %, S: 10.33 /Q; 1H NMR (d6-DMSO): 812.0, broad s, 1H (COOH);
S 7.20, dd, 1 H (aryl H); 6 7.16, dt, 1 H (aryl H); S 6.96, dd, 1 H(aryl H); 8 6.93, dt, 1 H (aryl H); S 3.80, s, 3H
(OCH3); S 2.85, t, 2H (CH2 a to S); 6 2.18, t, 2H (CH2 a to COOH); 6 1.6-1.2, multiplet, 14H
(rest of CHZ`s).
Example 5 -- Preparation of 8- 2-H drox - hen lsulfan 1-octan.oic acid Com ound 5):
[98] To a 150 mL round bottom flask equipped with a reflux condenser and magnetic stir bar was added 8-(2-methoxy-phenylsulfanyl)-octanoic acid (4.32 g, 15.3 mmol) and 25 mL
methylene chloride. The mixture was cooled with an external ice bath. Boron tribromide solution (25 ml of a 1 M solution in methylene chloride, 25 mmol) was added and the external ice bath removed. After 10 minutes the reaction was heated to reflux for 10 minutes and allowed to cool to room temperature. Boron tribromide solution (25 ml of a 1 M
solution in methylene chloride, 25 mmol) was added and the reaction allowed to mix at room temperature for 15 minutes. The reaction was cooled with an external ice bath and then quenched with 75 mL of water. This mixture was allowed to stir at room temperature for 18 hours. The layers were separated and the aqueous layer was extracted with methylene chloride (2 X 40 mL). The organic layers were combined and washed with water (40 mL) and then brine solution (40 mL).
The organic layer was dried over sodium sulfate, filtered, and then the solvent removed under reduced pressure. The residue was dissolved in aqueous 1 N sodium hydroxide (25 mL) and SUBSTITUTE SHEET (RULE 26) diluted with 100 mL water. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 14 days. The brown solid was collected by suction filtration. Solid was dissolved in aqueous 1 N sodium hydroxide solution (25 mL) and diluted with 75 mL water.
The solution was acidified to pH 8 with aqueous 1 N hydrochloric acid and cooled to 4 C. The pH was the lowered slowly by the addition of 2-3 drops of aqueous 1 N
hydrochloric acid two times a day for 21 days at 4 C. At end of time period 5 mL of aqueous 1 N
hydrochloric acid was added to ensure pH 1 and solution allowed to set for 18 hours at 4 C. The off-white product and one solid brown chunk were collected by suction filtration and the brown chunk removed with forceps. The product (2.54 g, 62%) was isolated as an off-white solid, mp 49-50 C. Found:
C: 62.52 %, H: 7.35 % S: 101.91 %; C14H2003S requires C: 62.47 %, H: 7.52 %, S: 11.91 %; IH
NMR (d6-DMSO): 612.0, broad s, 1H (COOH); 59.70, s, 1H (Ar-OH); S 7.16, dd, 1H
(aryl H); 8 7.01, dt, 1H (aryl H); S 6.80, dd, 1H (aryl H); S 6.77, dt, 1H (aryl H); $
2.82, t, 2H (CH2 (L to S);
$ 2.18, t, 2H (CH2 a to COOH); S 1.6-1.2, multiplet, l OH (rest of CH2`s).
Example 6-- Preparation of 6- 2 5-Dimeth 1- hen lsulfan 1-hexanoic acid (Compound [99] To a 500 mL flask, equipped with a magnetic stir bar, was added ethyl 6-bromo-hexanoate (5.25 mL, 30 mmol), 2,5-dimethylbenzen.ethiol (4.0 mL, 30 mmol), and 100 mL ethyl alcohol. The reaction vessel was cooled with an external ice bath while potassium hydroxide (5.32 g, 95 ininol) was added. The external ice bath was removed and the reaction was allowed to stir at room temperature for 18 hours under a nitrogen atmosphere. Water (100 mL) was added and the reaction was allowed to mix at room temperature for an additional 18 hours. Ethyl alcohol was removed under reduced pressure. The remaining solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours. The product (6.39 g, 86%) was isolated by filtration as a white solid, mp 61-62 C. Found: C: 66.80 %, H:
8.00 % S: 12.68 %;
C14H2002S requires C: 66.63 %, H: 7.99 %, S: 12.71 %; IH NMR (d6-DMSO): (COOH, not visible due to water in sample); 6 7.08, s, 1H (aryl H); S 7.06, d, IH (aryl H); S 6.88, d, 1H (aryl H); 6 2.90, t, 2H (CH2 a to S); 6 2.26, s, 3H (aryl-CH3); S 2.21, s, 3H (Aryl-CH3); S 2.19, t, 2H
(CH2 a to COOH); d 1.65-1.35, multiplet, 6H (rest of CH2`s).
SUBSTITUTE SHEET (RULE 26) Example 7 -- Preparation 4- 2 5-Dirneth 1- hen 1sulfan 1-bu ric acid Com ound [100] Prepared analogously to Compound 6 with ethyl 4-bromobutyrate (2.88 mL, mmol), 2,5-dimethylbenzenethiol (2.0 mL, 15 mmol), potassium hydroxide (2.54 g, 45 mmol), and 100 mL ethyl alcohol. The product (2.87 g, 87%) isolated as an off-white solid, mp 61-62 C. Found: C. 64.18 %, H: 7.26 % S. 14.39 %; C12H1602S requires C: 64.06 %, H: 7.20 %, S:
14.25 %; 1 H NMR (d6-DMSO): $ 12.14, s, 1 H(COOH); 6 7.13, s, 1 H(aryl H); 6 7.08, d, 1 H
(aryl H); S 7.06, d, 1H (aryl H); 6 2.94, t, 2H (CH2 (I to S); 6 23 8, t, 2H
(CH2 a to COOH); 6 2.26, s, 3H (aryl-CH3); 6 2.22, s, 3H (Aryl-CH3); 6 1.78, quintuplet, 2H
(other CH2`s).
Example 8 -- Preparation of 10- 2-H drox - hen lsulfan 1-decanoic acid (Compound S:
[101] Prepared analogously to Compound 3 with 2-hydroxybenzenethiol (1.5 mL, mmol), ethyl 10-bromodecanoate (4.16 g, 15 mmol), potassium hydroxide (2.49 g, 44 mmol), 10 mL ethyl alcohol, aqueous I N sodium hydroxide solution (4 mL), and water (15 mL). Product was further purified by recrystallization from hexanes twice. The product (1.81 g, 41 %) was isolated as an off-white solid, mp 58-59 C. Found: C: 64.27 %, H: 8.07 % S:
10.61 %;
C16H2403S requires C: 64.32 %, H: 8.19 %, S: 10.73 %; 1H NMR (d6-DMSO): b 12.00, broad s, 1H (COOH); 6 9.70, broad s, 1H (Aryl-OH); 8 7.16, d, 1H (aryl H); 6 7.00, t, 1H (aryl H); S 6.77, multiplet, 2H (other aryl H's); 6 2.82, t, 2H (CH2 a to S); 6 2.18, t, 2H (CH2 a to COOH); 6 1.60-1.15, multiplet, 14H (rest of CHZ`s).
Example 9 -- Preparation of 3- 2 5-Dimeth l- hen lsuMfan 1- ro ionic acid (Compound 9):
[102] Prepared analogously to Compound 6 with 2,5-dimethylbenzenethiol (3.0 mL, 22 mmol), ethyl 3-bromopropionate (4.04 g, 22 mmol), potassium hydroxide (3.49 g, 62 mmol), 100 mL ethyl alcohol and water (20 mL). The product (2.57 g, 55%) was isolated as a white solid, mp 100-102 C. Found: C: 62.83 %, H: 6.76 % S: 15.29 %; CI 1H1402S requires C:
62.71 %, H:
6.72 %, S: 15.22 %; IH NMR (d6-DMSO): 6 12.40, broad s, 1H (COOH); 6 7.12, s, 1H (aryl H); S 7.08, d, 1H (aryl H); 8 6.92, d, 1H (aryl H); S 3.09, t, 2H (CH2 a to S); 6 2.53, t, 2H (CH2 a to COOH); 6 2.27, s, 3H (aryl-CH3); 6 2.22, s, 3H (Aryl-CH3).
SUBSTITUTE SHEET (RULE 26) Example 10 -- Preparation of 8-(4-Methoxy-phenylsulfanyl)-octanoic acid (Compound 10);
[103] Prepared analogously to Compound 6 with 4-methoxybenzenethiol (4.0 mL, mmol), ethyl 8-bromooctanoate (8.21 g, 33 mmol), potassium hydroxide (5.57 g, 99 mmol), lOOmL ethyl alcohol and water (65 mL). The product (8.76 g, 95%) was isolated as an off-white solid, mp 66-68 C. Found: C: 63.29 %, H: 7.72 % S: 11.27 %; C15H2203S requires C. 63.64 %, H: 7.86 %, S: 11.33%; 1H NMR (d6-DMSO): b 7.30, d, 2H (aryl H's); 6 6.90, d, 2H (aryl H's);
S 3.74, s, 3H (OCH3); S 2.83, t, 2H (CH2 a to S); S 2.17, t, 2H (CH2 a to COOH); 5 1.60-1.20, multiplet, 10H (rest of CH2`s).
Example 11 -- Preparation of 8-(4-Hydroxy-phenylsulfanyl)-octanoic acid (Compound 11):
[104] To a 500 mL flask, equipped with a magnetic stir bar and a 60-mL
addition funnel, was added 4-hydroxybenzenethiol (5.22 g, 41 mmol), potassium carbonate (7.03 g, 51 mmol), and 100 mL ethyl alcohol. The reaction vessel was cooled with an external ice bath.
The addition fuzuiel was charged with ethyl 8 -bromoo etanoate (10.41 g, 41 mmol) and 55 mL
ethyl alcohol. This was then added drop-wise to the reaction vessel over 1 hour. The reaction was allowed to warm to room temperature and stirred for 18 hours under a nitrogen atmosphere.
Ethyl alcohol was removed under reduced pressure. The residue was dissolved in 10 mL ethyl alcohol and 80 mL of aqueous 1 N sodium hydroxide solution and allowed to stir at room temperature for 18 hours. Solution was acidified to pH 1 with aqueous 1 N
bydrochloric acid and cooled to 4 C for 18 hours. The product (10.20 g, 92%) was isolated by filtration as an off-white solid, mp 94-95 C. Found: C: 61.79 %, H: 7.55 % S: 11.50 %; C14H2003S
requires C:
62.07 %, H: 7.55 %, S: 121.84 %; 1H NMR (d6-DMSO): cS 12.00, s, 1H (COOH); 6 10.55, s, 1H
(Aryl-OH); S 7.20, d, 2H (aryl H's); 6 6.72, d, 2H (aryl H's); S 2.77, t, 2H
(CH2 a to S); S 2.18, t, 2H (CH2 a to COOH); S 1.55-1.20, multiplet, lOH (rest of CH2`s).
Example 12 -- Preparation of 4-(2-H_ydroxy-phenylsulfanyl)-butyric acid (Compound 12):
[105] To a 250 mL round bottom was added 2-hydroxybenzenthiol (1.5 mL, 15 mmol), ethyl 4-bromobutyrate (2.14 mL, 15 mmol) and 100 mL ethyl alcohol. The mixture was cooled with an external ice bath. Potassium hydroxide (0.85 g, 15 mmol) was added and the mixture was allowed to warrn to room temperature and stirred for 18 hours. Aqueous 1 N
sodium hydroxide solution (80 mL) was added and the reaction allowed to mix at room temperature for SUBSTITUTE SHEET (RULE 26) 18 hours. Ethyl alcohol was removed under reduced pressure and the residue was acidifzed with aqueous 1 N hydrochloric acid solution to pH 7 and cooled to 4 C. The pH was lowered slowly by the addition of aqueous I N hydrochloric acid solution (1-3 drops a day for 60 days.) During this period, the reddish oily that initially forms was removed via pipette upon the initial formation of a white precipitate. The product (1.98 g, 62%) was isolated by suction filtration as an off-white solid, mp 77-78 C. Found: C: 56.54 %, H: 5.84 % S: 14.98 %;
C10Haz03S requires C: 56.58 %, H: 5.70 %, S: 15.11 %; 1H NMR (d6-DMSO): 612.1, broad s, IH
(COOH); 59.75, s, IH (Ar-OH); 6 7.19, dd, iH (aryl H); 8 7.02, dt, 1H (aryl H); 6 6.78, muitiplet, 2H (aryl H's); 6 2.85, t, 2H (CH2 a to S); S 2.34, t, 2H (CH2 a to COOH); S 1.72, quintuplet, 2H (other CH2).
Example 13 -- Pre aration of 4-Methox - hen lsulfan 1-acetic acid Com ound 13 :
[106] To a mini-block tube was added 4-methoxybenzenthiol (2.50 mL, 20 mmol), ethyl bromoacetate (2.28 mL, 20 mmol), potassium hydroxide (2.33 g, 42 mmol) and 30 mL ethyl alcohol. The mixture was stirred under nitrogen for 18 hours. 5 mL of water and 5 mL of aqueous 1 N sodium hydroxide solution were added. The reaction mixture was heated (84 C) for 3 hours under atmospheric conditions to remove a majority of the ethyl alcohol. The mixture was cooled to room temperature and acidified with aqueous 1 N hydrochloric acid to pH 1 and allowed to stir at room temperature for 18 hours. The product (3.22 g, 80%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 512.66, broad s, 1H
(COOH); 6 7.33, multiplet, 2H (aryl H); b 6.89, multiplet, 2H (aryl H); 8 3.71, s, 3H (-OCH3);
d 3.60, s, 2H (CH2).
Example 14 -- Preparation of 5- 4-Methox - hen lsulfan 1- entanoic acid Com ound 14 :
[107] Prepared analogously to Compound 13 with 4-methoxybenzenthiol (2.00 mL, mmol), ethyl 5-bromopentanoate (2.57 mL, 16 mmol), potassium hydroxide (1.98 g, 35 mmol) and 30 mL ethyl alcohol. The product (3.22 g, 80%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 511.95, broad s, 1H (COOH); S 7.26, multiplet, 2H
(aryl H); 6 6.85, multiplet, 2H (aryl H); 6 3.69, s, 3H (-OCH3); d 2.78, t, 2H (CH2 a to S); 6 2.15, t, 2H (CH2 a to COOH); fi 1.60-1.40, multiplet, 4H (rest of CHZ`s).
SUBSTITUTE SHEET (RULE 26) Example 15 -- Preparation of 6- 4-Methox - hen lsulfan 1-hexanoic acid (Compound 15 :
[108] Prepared analogously to Compound 13 with 4-methoxybenzenthiol (2.00 mL, mmol), ethyl 6-bromohexanoate (2.89 mL, 16 mmol), potassium hydroxide (1.98 g, 35 mmol) and 30 mL ethyl alcohol. The product (3.34 g, 80%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): (COOH); S 7.40, multiplet, 2H (aryl H); 6 7.00, multiplet, 2H (aryl H); S 3.83, s, 3H (-OCH3); 6 2.91, t, 2H (CH2 a to S); 6 2.26, t, 2H (CH2 a to COOH); S 1.65-1.40, multiplet, 6H (rest of CH2`s).
Example 16 -- Preparation of 7- 2-Methox - hen yisulfan 1-he tanoic acid Com ound 16 :
[109] Prepared analogously to Compound 6 with 2-methoxybenzenethiol (1.4 mL, mmol), ethyl 7-bromoheptanoate (2.2 mL, 11 mmol), 30 mL ethyl alcohol, potassium hydroxide (1.9 g, 34 mmol), and 25 mL water. Crude product was further purified by dissolving in 10 mL
of aqueous 1 N sodium hydroxide solution and 100 mL of water and then acidifying solution to pH 1 with aqueous I N hydrochloric acid. Product (2.2 g, 73%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): 6 12.0, broad s, 1H (COOH); 6 7.19, dd, 1H
(aryl H); 6 7.13, dt, 1 H (aryl H); 6 6.9, multiplet, 2H (aryl H); S 3. 8, s, 3H (OCH3); 6 2.8, t, 2H (CHZ a to S);
b 2.2, 2H (CH2 a to COOH); 6 1.6-1.2, complex, 8H (rest of CH2's).
Example 17 -- Preparation of 4- 4-Metb.ox - henvlsulfan 1-bu ric acid Com ound 17):
[110] Prepared analogously to Compound 13 with 4-methoxybenzenthiol (2.00 mL, mmol), ethyl 4-bromobutyrate (2.33 mL, 16 mmol), potassium hydroxide (1.96 g, 35 mmol) and 30 mL ethyl alcohol. The crude product was dissolved in aqueous I N sodium hydroxide solution (10 mL) and 10 mL water. The cloudy aqueous layer was decanted off from the insoluble viscous yellow-brown oil and was then acidified to pH 1 with aqueous I N
hydrochloric acid. The product (2.72 g, 74%) was isolated by filtration as a white solid. 1H
NMR (d6-DMSO): 511.95, broad s, 1H S 12.08, s, IH (COOH); S 7.31, multiplet, 2H (aryl H); 6 6.91, multiplet, 2H (aryl H); S 3.74, s, 3H (-OCH3); 6 2.84, t, 2H (CH2 a to S); 8 2.33, t, 2H (CH2 a to COOH); S 1.70, p, 2H (last CH2).
SUBSTITUTE SHEET (RULE 26) Example 18 -- Preparation of 3- 4-Methox - hen lsulfan 1- ro ionic acid (Compound 18 :
[111] Prepared analogously to Compound 17 with 4-methoxybenzenthiol (2.50 mL, mmol), ethyl 3-bromopropanoate (2.61 mL, 20 mmol), potassium hydroxide (2.39 g, 42 mmol) and 30 mL ethyl alcohol. The product (2.30 g, 53%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 8 12.29, s, 1H (COOH); 6 7.33, multiplet, 2H (aryl H); 6 6.92, multiplet, 2H (aryl H); S 3.74, s, 3H (-OCH3); 6 2.99, t, 2H (CH2 a to S); S
2.44, t, 2H (CH2 a to COOH).
19 :
Example 19 -- Preparation of 5- 2-Methox - hen lsulfan 1- entanoic acid (Compound [112] Prepared analogously to Compound 6 with 2-methoxybenzenethiol (1.5 mL, 12.5 mmol), ethyl 5-bromovalerate (2.0 mL, 12.5 mmol), 25 mL ethyl alcohol, potassium hydroxide (2.0 g, 37 mmol), and 15 mL water. Product (2.6 g, 87%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.0, broad s, 1 H(COOH); S 7.2, dd, 1 H(aryl H); 7.14, dt, 1H (aryl H); 6 6.9, 2H (aryl H); 6 3.8, s, 3H (OCH3); S 2.85, t, 2H (CH2 a to S); S 2.2, t, 2H (CH2 a to COOH); S 1.7-1.5, complex, 4H (rest of CH2's).
Example 20 -- Preparation of 10- 3-Methox - hen lsulfan yl -decanoic acid (Compound 20 :
[113] Prepared analogously to Compound 6 with 3-methoxybenzenethiol(1.2 mL, 9.7 mmol), ethyl 10-bromodecanoate (2.3 mL, 9.7 mmol), 45 mL ethyl alcohol, potassium hydroxide (1.6 g, 29 mmol), and 15 mL water. Product (2.6 g, 88%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.0, broad s, IH (COOH); S 7.2, t, 1H (aryl H); 8 6.8, multiplet, 2H (aryl H); 6 6.7, dd, 1H (aryl H); 8 3.7, s, 3H (OCH3); d 29, t, 2H (CH2 a to S); b 2.15, t, 2H (CH2 a to COOH); S 1.6-1.1, complex, 14H (rest of CHZ's).
Example 21 -- Preparation of 6- 3-Methox - hen lsulfan 1-hexanoic acid (Compound 21):
[114] Prepared analogously to Compound 6 with 3-methoxybenzenethiol (2.0 mL, mmol), ethyl 6-bromohexanoate (2.9 mL, 16 mmol), 35 mL ethyl alcohol, potassium hydroxide (2.7 g, 49 mmol), and 20 mL water. The product (3.7 g, 89%) was isolated as a white powder by filtration. 11I NMR (d6-DMSO): S 7.19, t, 1H (aryl H); 8 6.83, multiplet, 2H
(aryl H); S 6.71, dd, 1H (aryl H); b 3.72, s, 3H (OCH3); S 2.92, t, 2H (CH2 a to S); 6 2.15, t, 2H (CH2 a to COOH); 8 1.6-1.3, complex, GH (rest of CHZ's).
SUBSTITUTE SHEET (RULE 26) Example 22 -- Preparation of $- 3-Methox - hen lsulfan 1-hexanoic acid (Compound 22):
[115] Prepared analogously to Compound 6 with 3-methoxybenzenethiol (1.5 mL, mmol), ethyl 8-bromooctanoate (2.6 mL, 12 mmol), 30 mL ethyl alcohol, potassium hydroxide (2.0 g, 36 mmol), and 15 mL water. Ethyl alcohol was distilled at atmospheric pressure. The crude product was further purified by dissolving in 10 mL aqueous I N sodium hydroxide solution and 100 mL of water. The solution was acidified to pH 1 with aqueous I N
hydrochloric acid. The product (2.9 g, 93%) was isolated as a white solid by filtration. 1H NMR
(d6-DMSO): S 12.0, broad s, 1H (COOH); 6 7.2, t, IH (aryl H); S 6.83, multiplet, 2H (aryl H); 6 6.71, dd, 1H (aryl H); $ 3.72, s, 3H (OCH3); 8 2.93, t, 2H (CH2 a to S); S
2.16, t, 2H (CH2 a to COOH); S 1.6-1.2, complex, lOH (rest of CH2's).
Example 23 -- Pre aration of 3-Chloro- hen lsulfan 1-acetic acid (Compound 23 :
[116] Prepared analogously to Compound 13 with 3-chlorobenzenethiol (2.00 mL, mmol), ethyl bromoacetate (1.91 mL, 17 mmol), potassium hydroxide (3.04 g, 54 mmol) and 40 mL ethyl alcohol. Hydrolysis step used 20 mL water and 10 mL of aqueous 1 N
sodium hydroxide solution and was heated to 55 C for 5 hours. The product (3.11 g, 89%) was isolated by filtration as a white solid. 1H NMR (d6-DMSO): 512.85, broad s, 1H (COOH);
b 7.39, t, 1H
(aryl H); S 7.33, t, 1H (aryl H); 6 7.28, dt, 1H (aryl H); b 7.24, dt, 1H
(aryl H); 8 3.88, s, 2H
(CH2).
Example 24 -- Preparation of 5- 3-Chloro- hen Isulfan I- entanoic acid Com ound 24):
[117] Prepared analogously to Compound 23 with 3-chlorobenzenthiol (2.00 mL, mmol), ethyl 5-bromopentanoate (2.72 mL, 17 mmol), potassium hydroxide (3.10 g, 55 mmol) and 30 mL ethyl alcohol. The product (3.73 g, 88%) was isolated by filtration as a white solid.
IH NMR (d6-DMSO): 612.85, broad s, 1H (COOH); S 7.35, t, 1H (aryl H); 6 7.32, t, 1H (aryl H); 6 7.26, dt, 1H (aryl H); 6 7.21, dt, 1H (aryl H); 8 3.01, t, 2H (CH2 ca to S); b 2.24, t, 2H (CH2 a to COOH); 6 1.7-1.5, complex, 4H (rest of CH2's).
Example 25 -- Preparation of 5- 2-Chloro- hen lsulfan 1- entanoic acid (Compound 25):
[118] Prepared analogously to Compound 23 with 2-chlorobenzenthiol (2.00 mL, mmol), ethyl 5-bromopentanoate (2.80 mL, 1$ mmol), potassium hydroxide (3.10 g, 55 mmol) SUBSTITUTE SHEET (RULE 26) and 30 mL ethyl alcohol. The product (3.86 g, 89%) was isolated by filtration as a white solid.
1H NMR (d6-DMSO): 512.03, s, lH (COOH); 6 7.44, dd, 1H (aryl H); 6 7.38, dd, 1H (aryl H); 6 7.33, dt, 1H (aryl H); d 7.18, dt, 1H (aryl H); 8 3.00, t, 2H (CH2 a to S); S
2.26, t, 2H (CH2 a to COOH); S 1.7-1.6, complex, 4H (rest of CH2's).
26 :
Exam le 26 -- Preparation of 6- 2-Chloro- hen lsulfan 1-hexanoic acid (Compound [119] Prepared analogously to Compound 23 with 2-chlorobenzenthiol(2.00 mL, 18 inmol), ethyl5-brornopentanoate (3.14 mL, 18 mmol), potassium hydroxide (3.04 g, 54 mmol) and 30 mL ethyl alcohol. The product (4.25 g, 93%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 611.99, s, 1H (COOH); 6 7.44, dd, 1H (aryl H); 6 7.37, dd, 1H (aryl H); 6 7.33, dt, 1H (aryl H); 6 7.17, dt. 1H (aryl H); 6 2.99, t, 2H (CH2 a to S); 6 2.20, t, 2H (CH2 a to COOH); S 1.7-1.3, complex, 6H (rest of CH2's).
Example 27 -- Preparation of 4- 3-Methox - hen lsulfan 1-bu ric acid (Compound 27):
[120] Prepared analogously to Compound 6 with 3-methoxybenzenethiol (1.7 mL, mmol), ethyl 4-bromobutyrate (1.9 mL, 13 mmol), 25 mL ethyl alcohol, and potassium hydroxide (2.5 g, 44 mmol). Reaction was allowed to stir under nitrogen atmosphere for 10 days. Water (15 mL) was added and the reaction was allowed to mix for 5 hours.
Ethyl alcohol was distilled off under atmospheric pressure. The residual was diluted with water (10 mL) was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours. The crude product, isolated by filtration, was further purified by dissolving in 10 mL
aqueous 1 N sodium hydroxide solution and 100 mL of water. The solution was then acidified to pH
1 with aqueous I N hydrochloric acid and crude product collected by filtration. The crude product was then dissolved in 10 mL aqueous 1 N sodium hydroxide solution and 100 mL of water.
The solution was then slowly acidified step wise to pH 7, pH 6, pH 5 and finally to pH 1 by the addition of aqueous 1 N hydrochloric acid. At each step the small amount of yellow oil that precipitated was removed via pipette. Product (1.6 g, 52%) was isolated as off=whi'te solid by filtration. 1 H NMR
(d6-DMSO): S 12.1, broad s,1 IH (COOH)6 7.17, t, 1 H(aryl H); S 6.83, multiplet, 2H (aryl H); S
6.7, dd,1H (aryl H); 6 3.7, s, 3H (OCH3); 6 2.9, t, 2H (CH2 a to S); 2.3, t, 2H (CH2 a to COOH);
S 1.73, quintet, 2H (remaining CH2).
SUBSTITUTE SHEET (RULE 26) Exam le 28 -- Preparation of 2-Chloro- hen 1sulfan 1-acetic acid (Compound 28):
[121] To a mini-tube equipped with a inagnetic stir bar, was added 2-chlorobenzene thiol (1.0 mL, 8.8 mmol), ethyl bromoacetate (0.98 mL, 8.8 mmol), and 35 mL
ethyl alcohol.
Potassium hydroxide (1.5 g, 24 mmol) was added at room temperature. Reaction was stirred at room temperature under nitrogen atmosphere for 18 hours. Water (20 mL) was added and the reaction stirred for 3 hours. Ethyl alcohol was distilled at atmospheric pressure and the residual was diluted with 100 mL of water. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 2 hours. The product (1.2 g, 61 %) was isolated as white powder by filtration. 1H NMR (d6-DMSO): 6 12.9, broad s, 1H (COOH); 6 7.4, d, 1H (aryl H);
b 7.3, dd, 2H (aryl H); 6 7.15, multiplet, 1H (aryl H); 6 3.85, s, 2H (CH2).
Exam le 29 -- Preparation of a- 3-Chloro- hen lsulfan 1-bu ric acid Com ound 29):
[122] Prepared analogously to Compound 23 with 3-chlorobenzenthiol (2.00 mL, mmol), ethyl 4-bromobutyrate (2.47 mL, 17 mmol), potassium hydroxide (3.03 g, 54 mmol) and 30 mL ethyl alcohol. The crude product was further purified by dissolving in 20 mL of aqueous I N sodium hydroxide solution and 30 mL water. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid. The product (2.99 g, 75%) was isolated by filtration as a brownish solid. 1H NMR (d6-DMSO): 812.85, broad s, 1H (COOH); 6 7.37, t, 1H
(aryl H); 6 7.32, t, 1H (aryl H); 6 7.27, dt, IH (aryl H); S 7.22, dt, 1H (aryl H); 6 3.01, t, 2H (CH2 a to S); b 2.35, t, 2H (CH2 a to COOH); 6 1.77, pentet, 2H (other CH2's).
Example 30 -- Preparation of 8- 2-Chloro- hen lsulfan 1-octanoic acid (Compound 30 :
[123] To a mini-tube equipped with a magnetic stir bar, was added 2-chlorobenzene thiol (1.0 mL, 8.2 mmol), ethyl 8-bromooctanoate (1.8 mL, 8.2 mmol), and 45 mL
ethyl alcohol.
Potassium hydroxide (1.5 g, 26 mmol) was added at room temperature and the reaction was allowed to stir at room temperature for 1 hr under a nitrogen atmosphere.
Water (10 mL) was added and the stirring continued for 3 hours. The reaction was heated to 45 C
for 0.5 hr, cooled to room temperature and stirred for an additional 96 hours. Solvent was removed under reduced pressure and the resulting solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 45 min. Product (2.24 g, 88%) was isolated as a white powder by filtration.
1H NMR (d6-DMSO): S 11.96, broad s, 1H (COOH); 6 7.42, dd,1H (aryl H); 6 7.33, multiplet, SUBSTITUTE SHEET (RULE 26) 2H (aryl H); 6 7.16, dt, 1H (aryl H); 6 2.97, t, 2H (CH2 a to S); S 2.17, t, (CH2 a to COOH); S
1.6-1.25, complex, l OH (rest of CHZ's).
Exam le 31 -- Preparation of 4- 2-Chloro- hen lsulfan 1-bu ric acid (Compound 31):
[124] Prepared analogously to Compound 30 with 2-chlorobenzenthiol (1 mL, 8.2 mmol), ethyl 4-bromobutyrate (1.3 mL, 8.2 mmol), 45 mL ethyl alcohol, and potassium hydroxide (1.5 g, 27 mmol). The product (0.92 g, 45 %) was isolated by filtration as a white powder. 1H NMR (d6-DMSO): 6 12.1, broad s, 1H (COOH); 6 7.38, multiplet, 2H
(aryl H); S
7.27, dt, 1H (aryl H); 6 7.12, dt, 1H (aryl H); 6 2.96, t, 2H (CH2 a to S); 6 2.33, t, 2H (CH2 a to COOH); 6 1.75, quintet, 2H (remaining CH2).
Example 32 -- Preparation of 6- 3-Chloro- hen isulfan 1-hexanoic acid (Compound 32):
[125] Prepared analogously to Compound 30 with 3-chlorobenzenethiol (1.0 mL, 8.6 mmol), ethyl 6-bromohexanoate (1.5 mL, 8.6 mmol), 45 mL ethyl alcohol, and potassium -hydroxide (1.5 g, 26 mmol). The product (1.9 g, 84 %) was isolated by filtration as a white powder. 1H NMR (d6-DMSO): 6 11.94, broad s, IH (COOH); S 7.28, t, 1H (aryl H);
S 7.26, d, 1H (aryl H); 6 7.2, dt, 1H (aryl H); b 7.16, dt, 1H (aryl H); S 2.95, t, 2H
(CH2 a to S); 6 2.14, t, 2H (CH2 a to COOH); 51.55-1.3, complex, 6H (rest of CH2's).
Example 33 -- Preparation of 8- 4-Chloro- hen lsulfan 1-octanoic acid (Compound 33):
[126] To a 250 mL round bottom flask, equipped with a magnetic stir bar, was added 4-chlorobenzenethiol (5.00 g, 35 mmol), ethyl 8-bromooctanoate (8.68 g, 35 mmol), potassium hydroxide (3.87 g, 69 mmol), and 100 znL methylene chloride. The mixture was stirred at room temperature for 24 hours. The solvent was removed by filtration and the resulting solid was dissolved in 150 mL water. The solution was adjusted to pH 7 with aqueous 1 N
hydrochloric acid. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product (0.20 g, 2%) as an off-white solid, mp 92-93 C.
Found: C: 58.55 %, H:
6.61 % S: 11.41 %, Cl: 12.01%; C1aHa9ClOZS requires C: 58.63 10, H: 6.68 %, S. 11.18 %, Cl:
12.36%; lH NMR (d6-DMSO):67.35, multiplet, 4H (aryl H's); 6 2.95, t, 2H (CH2 a to S); b 2.15, t, 2H (CH2 a to COOH); 6 1.7-1.1, multiplet, I OH (rest of CH2's).
SUBSTITUTE SHEET (RULE 26) Example 34 -- Preparation of 4- 4-Chloro- hen lsulfan 1-bu ric acid (Compound 34 :
[ 127] To a 250 mL round bottom flask, equipped with a magnetic stir bar, was added 4-chlorobenzenethiol (5.00 g, 35 mmol), 4-bromobutyric acid (5.77 g, 35 mmol), potassium hydroxide (1.94 g, 35 mmol), and 100 mL tetrahydrofuran. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered to remove solid byproducts and the solvent was removed under reduced pressure. Crystallization from methyl alcohol:water (3:1) yielded the product (2.10 g, 26%) as an off-white solid, mp 100-101 C. Found:
C: 52.17 %, H:
4.75 % S: 13.53 %, Cl: 15.28%; CIoH11C102S requires C: 52.05 %, H: 4.81 %, S:
13.89 %, Cl:
15.37%; 1H NMR (d6-DMSO): 57.35, multiplet, 4H (aryl H's); b 3.00, t, 2H (CH2 a to S); S
2.40, t, 2H (CH2 a to COOH); 8 1.75, multiplet, 2H (other CH2).
Example 35 -- Preparation of 6- 4-H drox - hen lsulfan 1-hexanoic acid (Compound 35 :
[128] To a 125 mL round bottom flask, equipped with a magnetic stir bar, was added 4-hydroxybenzenethiol (5.00 g, 40 mmol), 6-bromohexanoic acid (7.73 g, 40 mmol), triethylamine (11.08 mL, 79 mmol), and 30 mL tetrahydrofuran. The reaction was stirred at room temperature for 96 hours. The solvent was removed under reduced pressure. The residual was dissolved in water (100 mL) and acidified with aqueous 1 N hydrochloric acid solution to pH
2. The precipitate was collected by filtration. Recrystallization from acetonitrile/water yielded the product (3.10 g, 33%) as an off-white solid, mp 92-94 C. Found: C: 59.88 %, H:
6.62 % S:
13.23 %; C12H1603S requires C: 59.97 %, H: 6.71 %, S: 13.34 %; IH NMR (d6-DMSO): 57.20, multiplet, 2H (aryl H's); 56.75, multiplet, 2H (aryl H's); b 2.80, t, 2H (CH2 a to S); S 2.20, t, 2H
(CHZ a to COOH); S 1.7-1.3, multiplet, 6H (rest of CH2's).
Example 36 -- Preparation of 4- 3-H drox - hen lsulfan 1-bu ric acid (Compound 36):
[129] To a mini-tube equipped with a magnetic stir bar, was added 3-mercaptophenol (0.96 mL, 9.4 mmol), 15 mL ethyl alcohol, 5 mL water, and potassium carbonate (1.6 g, 12 mmol). Ethyl 4-bromobutyrate (1.35 mL, 9.4 mmol) was added drop-wise and the reaction was allowed to stir at room temperature under a nitrogen atmosphere for 20 minutes. Aqueous 1 N
sodium hydroxide solution (28 mL) was added and the reaction was allowed to stir at room temperature for 18 hours. The mixture was heated to 45 C for 3 hours, cooled to room temperature and stirred under a nitrogen atmosphere for 48 hours. Ethyl alcohol was distilled at SUBSTITUTE SHEET (RULE 26) atmospheric pressure and the residue was dissolved in aqueous 1 N sodium hydroxide solution (10 mL) and diluted with 100 mL water. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 1 hr. The product (1.4 g, 72%) was isolated as a tan solid by filtration. 1H NMR (d6-DMSO): 6 12.0, broad s, 1H (COOH); 8 9.5, broad s, 1H (Ar-OH); S 7.1, t, 1H (aryl H); 6 6.7, multiplet, 2H (aryl H); 6 6.5, dd, 1H (aryl H); S 2.9, t, 2H (CH2 a to S); 6 2.3, t, 2H (CH2 a to COOH); S 1.75, quintet, 2H (remaining of CH2's).
Exam le 37 - Preparation of 843-Hydroxy-pheny 1sulfany 1-octanoic acid (Compound 37):
[130] Prepared analogously to Compound 36 with 3-mercaptophenol (0.85 mL, 8.3 mmol), potassium carbonate (1.4 g, 10.4 mmol), ethyl 8-bromooctanoate (1.75 mL, 8.3 mmol), 15 mL ethyl alcohol, and 5 mL water for first step of reaction. Aqueous 1 N
sodium hydroxide (25 mL, 25 mmol) was used for second reaction step. Crude product was further purified by dissolving in 10 mL aqueous 1 N sodium hydroxide solution and 100 mL water.
The solution was then acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours.
Product (1.9 g, 84%) was isolated as an off-white powder by filtration. 1H NMR
(d6-DMSO): S
7.3, t, 1H (aryl H); 6 6.65, multiplet, 2H (aryl H); S 6.5, dd, 1H (aryl H), 52.8, t, 2H (CH2 a to S);
6 2.1, t, 2H (CH2 a to COOH); 6 1.5-1.2, complex, lOH (rest ofCH2's).
Example 38 -- Preparation of lU- 4-H drox - hen lsulfan 1-decanoic acid Com ound 38).
[131] Prepared analogously to Compound 36 with 4-hydroxythiophenol (0.76 mL, 6.8 mmol), potassium carbonate (3.7 g, 27 mmol), ethyl 10-bromodecanoate (1.6 mL, 6.Smmo1), 15 mL ethyl alcohol, and 5 mL water for first step of reaction, Aqueous 10 N
sodium hydroxide solution (2.0 mL, 20 mmol) was used for second reaction step.. The product (1.26 g, 63%) was isolated as a tan solid by filtration. 1H NMR (deuterium oxide with NaOD
added): 6 7.0, multiplet, 2H (aryl H); 6 6.4, multiplet, 2H (aryl H); 6 2.6, broad t, 2H (CH2 a to S); 6 1.95, broad t, 2H (CH2 a to COOH); b 2.0-1.0, complex, 14H (rest of CH2's).
Example 39 -- Preparation of 10- 3-H drox -- hen lsulfan 1-decanoic acid (Compound 39 :
[132] Prepared analogously to Compound 36 with 3-mercaptophenol (0.85 mL, 8.3 mmol), potassium carbonate (1.4 g, 10 mmol), ethyl 10-bromodecanoate (2.0 mL, 8.3 mmol), 15 mL ethyl alcohol, and 5 mL water for first step of reaction. Aqueous 1 N
sodium hydroxide SUBSTITUTE SHEET (RULE 26) solution (25 mL, 25 mmol) was used for second reaction step. The crude product was further purified by dissolving in 10 mL of aqueous 1 N sodium hydroxide solution and 100 mL water.
The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 3 hours. Product (2.1 g, 85%) was isolated an off-white solid by filtration. 1H
NMR (d6-DMSO):
8 7.0, t, 1H (aryl H); 6 6.64, multiplet, 2H (aryl H); 6 6.5, dd, IH (aryl H);
S 2.83, t, 21-1(CH2 a to S); S 2.1, t, 2H (CH2 a to COOH); fi 1.5-1.1, complex, l OH (rest of CHZ's).
Example 40 -- Preparation of (2,5-dichloro-phenylsulfanyl)-acetic acid (Compound 40~
[133] To a mini-tube equipped with a magnetic stir bar, was added 2,5-dichlorobenzenethiol (1.1 mL, 8.3 mmol), 20 mL ethyl alcohol, 10 mL water, and potassium hydroxide (1.4 g, 25 mmol). The reaction was stirred under a nitrogen atmosphere for 20 min then ethyl bromoacetate (0.92 mL, 8.3 mmol) was added. The reaction was heated to 45 C for 1 hour. Ethyl alcohol (5 mL) and water (2 mL) were added to dissolve fonned precipitate and the reaction was allowed to stir for 48 hours. Ethyl alcohol was distilled at atmospheric pressure and the residue was dissolved in aqueous 1 N sodium hydroxide solution (10 mL) and diluted with 100 mL water. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 3 days. Product (1.7 g, 88%) was isolated as a white powder by filtration. 1H
NMR (d6-DMSO): 6 7.46, d, 1H (aryl H); 6 7.35, d, IH (aryl H); S 7.23, dd, 1H
(aryl H); S 4.0, s, 2H (CH2).
Example 41 -: Preparation of 6-(2,5-dichloro-phenylsulfan_yl)-hexanoic acid (Compound 41~
[134] Prepared analogously to Compound 40 with 2,5-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 6-bromohexanoate (1.5 mL, 8.3 mmol). Precipitate did not form during initial reaction step;
extra ethyl alcohol and water were not required. Product (2.1 g, 88%) was isolated as a white powder by filtration. 1H NMR (d6-DMOS): S 11.9, broad s, 1H (COOH); 6 7.4, d, IH (aryl H);
6 7.28, d, 1H (aryl H)a 6 7.14, dd, 1H (aryl H); 6 2.95, t, 2H (CH2 a to S); 6 2.1, t, 2H (CHZ a to COOH); 6 1.6-1.3, complex, 6H (rest of CH2's).
SUBSTITUTE SHEET (RULE 26) Example 42 -- Preparation of 3 4-dich.loro- hen yisulfan 1-acetic acid (Compound 42):
[135] Prepared analogously to Compound 40 with 3,4-d.ichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl bromoacetate (0.92 mL, 8.3 mmol). Precipitate did not form during initial reaction step; extra ethyl alcohol and water were not required. Product (1.6 g, 83%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.9, broad s, IH (COOH); b 7.55, d, 1H
(aryl H); b 7.51, d, 1H (aryl H); 8 7.27, dd, 1H (aryl H); S 3.9, s, 2H (CHZ).
Example 43 -- Preparation of b- 3 4-dichloro-hen lsulfan 1-hexanoic acid (Compound 43 :
[136] Prepared analogously to Compound 40 with 3,4-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 6-bromohexanoate (1.5 mL, 8.3 mmol). Precipitate did not form during initial reaction step;
extra ethyl alcohol and water were not required. Product (0.75 g, 31 %) was isolated as a white solid by filtration. 1H NMR (d6-DMSO): S 11.9, s, 1H (COOH); S 7.5, multiplet, 2H (aryl H); b 7.2, dd, 1 H(aryl H); S 2.95, t, 2H (CH2 a to S); S 2.15, t, 2H (CH2'a to COOH); & 1.6-1.3, 6H
(rest of CHZ's).
Example 44 -- Preparation of 3- 2-Chloro- hen lsulfan 1- ra ionic acid (Compound 44):
[137] To a 500 mL round bottom flask, equipped with a magnetic stir bar, was added 2-chlorobenzenethiol (2.00 mL, 18 mmol), ethyl 3-bromopropionate (2.26 mL, 18 mmol), potassium hydroxide (2.08 g, 37 mmol), and 50 mL ethyl alcohol. The reaction mixture was stirred at room temperature for 4 hours, 15 mL water was added and the mixture was stirred for 42 hours at room temperature. Ethyl 3-bromopropionate (1.70 rnL, 13 mmol) and potassium hydroxide (2.19 g, 39 mmol) were added in three aliquots during the next 18 hours. Solvent was removed under reduced pressure. Residual was dissolved in 150 mL water and acidified with aqueous 1 N hydrochloric acid solution to pH 1. Filtration yielded the product (3.56 g, 93%) as a white solid. IH NMR (d6-DMSO): S 12.41, s, 1H (COOH); 6 7.46, dd, 1H (aryl H);
6 7.40, dd, 1H (aryl H); 6 7.34, dt, 1H (aryl H); d 7.20, dt, 1H (aryl H); S 3.18, t, 2H
(CH2 ato S); & 2.59, t, 2H (CH? a to COOH).
SUBSTITUTE SHEET (RULE 26) Example 45 -- Preparation of 3- 3-Chloro- hen lsulfanvl - ro ionic acid (Compound 45 :
[138] Prepared analogously to Compound 44, with 3-chlorobenzenethiol (2.0 mL, mmol), ethyl 3-bromopropionate (2.21 mL, 17 mmol), potassium hydroxide (2.01 g, 36 mmol), 50 mL ethyl alcohol. For aliquots: ethyl3-bromopropionate (1.70 mL, 13 mmol) and potassium hydroxide (2.22 g, 39 mmol) were used. Filtration yielded the product (3.24 g, 88%) as a white solid. 1H NMR (d6-DMSO): S 12.38, s, 1H (COOH); S 7.38, t, 1H (aryl H); 6 7.34, t, IH (aryl H); S 7.28, dt, 1 H (aryl H); & 7.24, dt, I H (aryl H); S 3.18, t, 2H (CH2 a to S); 8 2. 55, t, 2H (CH2 a to COOH).
Exam le 46 -- Preparation of 3-H drox - hen lsulfan 1-acetic acid Com ound 46):
[139] Prepared analogously to Compound 36 with 3-mercaptophenol (1.1 mL, l lmmol), potassium carbonate (1.9 g, 14 mmol), and ethyl bromoacetate (1.2 mL, 11 mmol).
Product did not precipitate from acidic solution. Aqueous acid solution was extracted with ethyl acetate (3 X 50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered to remove drying agent and solvent removed under reduced pressure.
Residual acetic acid was removed by azeotroping with toluene (4 X 100 mL) to yield the product (1.4 g, 70%) as a tan solid. IH NMR (d6-Acetone): 6 7.1, t, 1H (aryl H); S 6.8, multiplet, 2H
(aryl H); 86.6, dd, 1 H (aryl H); b 3.7, s, 2H (CH2).
Example 47 -- Preparation of 2-Fluoro- hen lsulfan 1-acetic acid (Compound 47 [140] Prepared analogously to Compound 40 with 2-fluorothiophenol (1.2 mL, 1lmmol), potassium hydroxide (1.8 g, 32 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl bromoacetate (1.2 mL, l lmmol). Product (1.3 g, 67%) was isolated as a white powder by filtration. IH NMR (d6-DMSO): d 13.0, s, 1 H(COOH); 6 7.38, dt, 1 H(aryl H); 8 7.25-7.1, multiplet, 3H (aryl H); 6 3.8, s, 2H (CHz).
Exam le 48 -- Preparation of 6- 2-Fluoro- hen lsulfan 1-hexanoic acid (Compound 48 :
[141] Prepared analogously to Compound 40 with 2-fluorothiophenol (0.88 mL, 8.2 i,nmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 6-bromohexanoate (1.5 mL, 8.2 mmol). Product (1.8 g. 88%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.0, s, 1H (COOH); S 7.4, dt, 1H (aryl H); S
7.25-7.1, SUBSTITUTE SHEET (RULE 26) multiplet, 3H (aryl H); 8 2.9, t, 2H (CH2 a to S); S 2.1, t, 2H (CHZ a to COOH); S 1.6-1.3, complex, 6H (rest of CH2's).
Example 49 -- Preparation of 6- 3-Fluoro- hen lsulfan 1-hexanoic acid (Compound 49):
[142] Prepared analogously to Compound 40 with 3-fluorothiophenol (0.70 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl 6-bromohexanoate (1.5 mL, 8.3 mmol). Product (1.4 g, 70%) was isolated as a white solid by filtration. 1H NMR (d6-DMSO): 6 12.0, s, 1H (COOH); S 7.3.dt, 1H (aryl H); 6 7.1, dt, 2H (aryl H); 6 6.9, dt, 1H (aryl H); 8 3.0, t, 2H (CH2 a to S); S 2.1, t, 2H (CH2 a to COOH); 6 1.6-1.3, complex, 6H (rest of CH2's).
1-bu ric acid Corn ound 50):
Exam le 50 -- Preparation of 4-(2,5-dichloro-phenylsulfany [143] Prepared analogously to Compound 40 with 2,5-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 4-bromobutyrate (1.2 mL, 8.3 mmol). Reaction was allowed to stir for 8 days under nitrogen atmosphere. Crude product was further purified by dissolving in 3 mL ethyl alcohol and 8 mL
aqueous 1 N sodium hydroxide and allowing to stir under nitrogen atmosphere for 48 hours. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 4 days.
The product (0.49 g, 22%) was isolated as a white solid by filtration. I H NMR
(d6-DMSO): S
12.2, s, 1 H (COOH); 6 7.4, multiplet, 2H (aryl H); 6 7.2, dd, 1 H(aryl H); S
3.0, t, 2H (CH2 a to S); 8 2.35, t, 2H (CH2 a to COOH); S 1.8, quintet, 2H (remaining CH2).
Example 51 -- Preparation of 3-Fluora- hen lsulfan 1-acetic acid (Compound 51 :
[144] Prepared analogously to Compound 40 with 3-fluorothoiphenol (0.9 mL, 11 mmol), potassium hydroxide (1.8 g, 32 mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl bromoacetate (1.2 mL, 11 mmol). The product (0.74 g, 37%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): 6 13.0, broad s,-1H -(COOH); 6 73, dt, 1H (aryl H); S 7.13, multiplet, 2H (aryl H); 6 6.96, dt, 1H (aryl H); 8 3,9, s, 2H (CH2).
SUBSTITUTE SHEET (RULE 26) Example 52 -- Preparation of 4- 3-Fluoro- hen lsulfan 1-bu ric acid (Compound 52):
[145] Prepared analogously to Compound 40 with 3-fluorothiophenol (0.8 mL, 9.4 mmol), potassium hydroxide (1.6 g, 28 mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl 4-bromobutyrate (1.5 mL, 11 mmol). After stirring under a nitrogen atmosphere for 4 days, a seco.nd portion of potassium hydroxide (0.5 g, 9.4 mmol) was added and stirring under a nitrogen atmosphere continued for an additional 18 hours. The product (0.94 g, 47%) was isolated as a white solid by filtration. 1H NMR (d6-DMSO): 6 12.0, s, 1H (COOH); S 7.25, dt, 1H (aryl H); 6 7.1, multiplet, 2H (aryl H); 6 6.9, dt, 1H (aryl H); 2.9, t, 2H (CHZ a to S);
6 2.9, t, 2H (CH2 a to COOH); $ 1.7, quintet, 2H (remaining CH2).
Example 53 -- Preparation of 4- 3 4-dich.loro- hen lsuÃlfan 1-bu ric acid (Compound 53).
[146] Prepared analogously to Compound 50 with 3,4-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 4-bromobutyrate (1.2 mL, 8.3 mmol). The crade product was further purified by dissolving in 50 mL aqueous I N sodium hydroxide, washing aqueous solution with diethyl ether (3 X 25 mL), acidifying to pH 1 with aqueous 6 N hydrochloric acid and extracting with diethyl ether (3 X 25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered to remove drying agent and the solvent removed under reduced pressure. The residue was dissolved in aqueous I N sodium hydroxide (10 mL), diluted with water (100 mL), acidified to pH 1 using aqueous 1 N hydrochloric acid, and cooled to 4 C for 18 hours. The product (0.73 g, 33%) was isolated as a white powder by filtration. IH NMR (d6-DMSO): & 12.0, broad s, 1H
(COOH); S 7.54, d, 1H (aryl H); 8 7.49, d, 1H (aryl H); 6 7.25, dd, 1H (aryl H); 8 3.0, t, 2H (CH2 a to S); 6 2.3, t, 2H (CH2 a to COOH); S 1.73, quintet, 2H (remaining CH2).
Example 54 -- Preparation of 4- 2-Fluoro- hen lsulfan 1-bu ric acid (Compound 54 :
[147] Prepared analogously to Compound 53 with 2-fluorothiophenol (1.0 mL, 9.4 mmol), potassium hydroxide (1.6 g, 28 mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl 4-bromobutyrate (1.5 mL, 11 mmol). Crude oily product was further purified by dissolving in 40 mL diethyl ether, adding silica-bound maleimide (1,1 g, 14 mmol), and stirring under a nitrogen atmosphere for 20 hours. The silica-bound maleimide scavenger was removed by filtration. The solution was extracted with aqueous 1 N sodium hydroxide solution (2 X 50 mL).
The combined SUBSTITUTE SHEET (RULE 26) aqueous layers were washed with diethyl ether (2 X 50 mL), acidified to pH 1 with aqueous 6 N
hydrochloric acid, and extracted with diethyl ether (2 X 50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered to remove drying agent, and the solvent removed under reduced pressure to yield the product (0.93 g, 46%) as an off-white solid. 1H NMR (d6-DMSO): 6 12.0, s, 1H (COOH); S 7.4, dt, IH (aryl H); 6 7.26-7.1, multiplet, 3H
(aryl H); 5 2.9, t, 2H (CH2 a to COOH); S 2.3, t, 2H (CH2 a to COOH); 1.7, quintet, 2H (remaining CH2).
Example 55 -- Preparation of 4-k'luoro- hen lsulfan 1-acetic acid (Compound 55 :
[148] Prepared analogously to Compound 40 with 4-fluorothiophenol (1.15 mL, 11 mmol), potassium hydroxide (1.8 g, 32 mmol), 20 mL ethyl alcohol, 5 mL water, and ethyl bromoacetate (1.2 mL, 11 nunol). The product (1.4 g, 70%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.7, s, IH (COOH); S 7.4, complex, 2H (aryl);
8 7.17, dt, 2H (aryl); S 3.75, s, 2H (CH2).
Example 56 -- Preparation of 4- 4-Fluoro- hen lsulfan 1-bu ric acid Com ound 56 :
[149] Prepared analogously to Compound 40 with 4-fluorothiophenol (1.0 mL, 9.4 mmol), potassium hydroxide (1.6 g, 28 mmol), 20 mL ethyl alcohol, 5 mL water, and ethyl 4-bromobutyrate (1.5 mL, 11 mmol). The reaction was allowed to stir under a nitrogen atmosphere for 18 hours, then potassium hydroxide (0.6 g, 10 mmol) was added and the stirring continued for an additional 48 hours. Ethyl 4-bromobutyrate (0.39 mL, 3 mmol) was added and the reaction was heated to 45 C for 90 minutes. The reaction was cooled to room temperature and allowed to mix under a nitrogen atmosphere for 18 hours. The ethyl alcohol was removed under reduced pressure and the residue was dissolved in aqueous 1N sodium hydroxide (10 mL) and diluted with water (100 mL). The solution was acidified to pH 1 using aqueous 1 N aqueous hydrochloric acid and cooled to 4 C for 18 hours. Filtration yielded the product (1.2 g, 61 %) as an off-white powder. 1H NMR (d-DMSO): 6 12.0, broad s, 1H (COOH); 6 7.35, complex, 2H
(aryl); S 7.13, dt, 2H (aryl); 6 2.9, t, 2H (CH2 a to S); 6 2.3; t, 2H (CH2 a to COOH); 6 1.7, quintet, 2H (remaining CHZ).
SUBSTITUTE SHEET (RULE 26) Example 57 -- Preparation of 6- 4-Fluoro- hen Isulfan 1-hexanoic acid (Compound S7 :
[150] Prepared analogously to Compound 40 with 4-fluorothiophenol (0.88 mL, 8.2 mmol), potassium hydroxide (1.4 g, 24 mmol), 20 mL ethyl alcohol, 5 mL water, and ethyl 6-bromohcxanoate (1.5 mL, 8.2 mmol). Filtration yielded the product (1.8 g, 88%) as a white powder. IH NMR (d6-DMSO): 6 12.0, s, 1 H(COOH); 6 7.37, complex, 2H (aryl); S
7.15, dt, 2H (aryl); S 2.9, t, 2H (CH2 a to S); S 2.17, t, 2H (CH2 a to COOH); 6 1.6-1.3, complex, 6H (rest of CHZ's).
Example 58 -- Preparation of 2 5-Dimeth 1- hen 1sulfan 1-acetic acid (Compound 58), [151] To a 250 mL round bottom flask equipped with a magnetic stir bar was added 2,5-dimethylbenzenethiol (3.5 mL, 25.8 mmol), ethyl bromoacetate (4.32 mL, 25.9 mmol), and 100 mL ethanol. Potassium hydroxide (4.44 g, 79.1 mmol) was added and allowed reaction to mix under nitrogen atmosphere for 18 hours. Water (50 mL) was added and the reaction was allowed to stir for another 18 hours under nitrogen atmosphere. Ethanol was removed under reduced pressure. The remaining solution was diluted with water, acidified to pH 1 with aqueous 1N
hydrochloric acid, and sonicated to form solid precipitate. The solution was cooled to 4 C for 18 hours. Filtered to collect crude product and re-suspended in 1.ON sodium hydroxide. Acidified solution with 1N hydrochloric acid to pH 4.5 and sonicated to form a precipitate. Continued adding 1N hydrochloric acid until pH 1. Solution was cooled to 4 C for 2 - 3 hours. Product (4.44 g, 88%) was isolated by filtration as a gel, mp 73-74 C. Found: C: 61.18 %, H: 6.34 %, S:16.26%; CjoH1202S requires C: 61.2 %, H: 6.16 %, S: 16.34%; 1H NMR (d6-DMSO):
(COOH, not visible due to water in sample); 6 7.09, d. 1H (aryl H); 6 7.06, s, 1H (aryl H); b 6.91, dd, 1H (aryl H); S 3.75, s, 2H (CH2); 6 2.24, s, 6H (aryl-CH3's).
Example 59 -- Preparation of 4- 2-Chloro- hen lsulfan lmeth 1-benzoic acid Com ound 59):
[152] Prepared analogously to Compound 33, but with 2-chloro-benzenethiol, 4-broinomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding SUBSTITUTE SHEET (RULE 26) the product. Found: C: 60.14 %, H: 3.97 % S: 11.42 %, Cl: 12.73 %. C14H1 102SC1 requires C:
60.32%,H:3.98 %, S: 11.50%,Cl: 12.71 %.
Example 60 -- Preparation of 4- 2-Methox - hen lsulfan lmeth l- hen 1-acetic acid (Compound 60):
[153] Prepared analogously to Compound 33, but with 2-methoxy-benzenethiol, (4-bromomethyl-phenyl)-acetic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 66.55 %, H: 5.41 % S: 11.07 %; C16H1603S requires C:
66.64 %, H: 5.59 %, S: 11.12 %.
Example 61 -- Preparation of 4- 2-Meth.ox - hen lsulfan lmeth 1-benzoic acid (Comuound 61):
[1541 Prepared analogously to Compound 33, but with 2-methoxy-benzenethiol, 4-Bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which fonned was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 65.66 %, H: 5.13 % S: 11.40 %; C15H1403S requires C:
65.67 %, H. 5.14 %, S: 11.69 %.
Example 62 -- Pre aration of 4-Phen lsulfan lmeth 1- hen 1-acetic acid (Compound 62 :
[155] Prepared analogously to Compound 33, but with benzenethiol, (4-bromomethyl-phenyl)-acetic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 69.53 %, H: 5.37 % S: 12.51 %; C15H1402S requires C: 69.74 %, H: 5.46 %, S: 12.41 %.
Example 63 -- Preparation of 4-Phen lsulfan lmeth 1-benzoic acid (Compound 63 :
[156] Prepared analogously to Compound 33, but with Benzenethiol, 4-Bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed wxth water (2 X 50 mL) yielding the product.
SUBSTITUTE SHEET (RULE 26) Found: C: 68.06 %, H: 4.91 % S: 12.67 %; C14Hi202S requires C: 68.73 %, H:
4.95 %, S: 13.11 %.
Example 64 Preparation of 4-(4-Chloro-phenylsulfanylmethyl)-benzoic acid (Compound 64)-.
[157] Prepared analogously to Compound 33, but with 4-chloro-benzenethiol, 4-bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 59.90 %, H: 3.92 % S: 11.30 %, Cl: 12.70 %; C14HI1O2SC1 requires C:
60.32 %, H: 3.98 %, S: 11.50 %, Cl: 12.72 %.
Example 65 -- Preparation of 4-(2-Hydroxy-phenylsulfanylmeth_yl)-benzoic acid (Compound 65):
[158] Prepared analogously to Compound 33, but with 2-mercapto-phenol, 4-Bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 64.75 %, H: 4.88 % S: 11.96 %; C14HI203S requires C:
64.60 %, H: 4.65 %, S: 12.32 %.
Example 66 -- Preparation of 4-(2-Hydroxy-phenylsulfanylmethyl)-benzoic acid (Compound 66):
[159] Prepared analogously to Compound 33, but with 2-mercapto-phenol, (4-bromomethyl-phenyl)-acetic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 65.41 %, H: 5.07 % S: 11.92 %; CE5H1403S requires C:
65.67 %, H: 5.14 %,S:11.69%.
Example 67 -- Oral delivery of Insulinto Male Sprague-Dawley Rats [160] Insulin stock solution (15 mg/ml) (Human zinc insulin, Calbiochem-Novabiochem Corp., La Jolla, CA) was prepared with deionized water. Oral dosing SUBSTITUTE SHEET (RULE 26) compositions containing 200 mg/kg of delivery agent compound and 0.5 mglkg of insulin in aqueous solution were prepared with the delivery agent compound shown in Table 1 below.
Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt with one equivalent of sodium hydroxide.
[161] The dosing solution was administered to fasted male Sprague-Dawley rats by oral gavage with an average weight of about 225-250 grams. Blood glucose levels were then determined by glucometer (One Touch UltraLifeScan, Inc.) and compared to vehicle control (1 ml/kg of water). Samples were collected prior to dosing (time 0) and at 15, 30, 45 and 60 minutes after dosing. The % glucose reduction values in Table 1 are values found at the C
minimum, and are an average % reduction with respect to the number of times the experiment was run for each delivery agent.
Table 1: Percent Change in Glucose Insulin 200mg/lcg Delivery Agent Compound; 0.5 rn/k Insulin Delivery % Glucose Delivery % Glucose Comg pouentnd Reduction Com pund Reduction 1 -0.2 28 -51.5 t 27.0 3 -212f9.7 28 -28.2 17.4 3 -25.7 ~ 22.7 28 -46.9 24.9 6 -9.8 f 30.4 29 -51.0 19.4 7 -8.6 t 7.2 29 -56.7 20.5 7 -20.0 29 -69.4 f 11.5 7 -29.0 30 -18.3 39.0 58 -18.2 30 -15.2 f 16.5 9 -6.0 t 12.9 31 -43.3 16.3 9 -34.6 31 -37.4 f 23.8 11 -55.8 7~ 17.9 32 -15.2 28.9 11 -25.8 8.2 36 -69.1 f 5.5 12 -40.2 f25.2 36 -39.4 f 34.9 12 . -54,8 f 46.3 36 -51.3 8.8 12 -35.3 f11.5 40 -6.0 17.5 13 -18.2 t17.4 42 -22.1 5.4 14 -13.9~2.9 44 -7.8f 16.5 14 -47.8f21.2 45 -6.5 21.2 14 -16.9f 16.3 46 0.3f27.7 16 -38.9 f 32.7 47 -31.2 19.4 17 -36.9118.2 47 -38.8-+ 8.7 SUBSTITUTE SHEET (RULE 26) Insulin 200m /k Delivery Agent Com ound; 0.5 m/k g Insulin Delivery % Glucose Delivery % Glucose A Comgeound Reduction C mg pent ound Reduction 17 -46.4 t 8.1 48 -43.1 20.0 17 -39.9 130.0 48 -30.5 :L 22.9 18 -23.5 29.0 48 -32,8 t 16.4 18 -22.5 14.6 49 -34.6 f 11.5 19 -33.6 32.4 49 -17.2 t 23.7 20 -33.9 f 41.8 50 -15.8 :~ 10.6 21 -19.4f6.6 51 -24.9 6.2 22 -3.7 9.4 52 -60.3 + 18.9 23 -67.6 f 6.4 52 -316 22.6 23 -21.015.3 53 -14.817.0 23 -38.4 26.2 54 -37.4 26.0 24 -10A +17.7 55 -20.9 17.5 25 -16.0-L 13.4 56 -4.5~11.1 27 -47.6t17.4 57 -11.0~15.7 [162] 0.5 mg/1Cg of Insulxn and 25 - 100 mg/kg of delivery agent compound (particular amount shown in Table 2 below) was administered to male Sprague-Dawley rats with an average weight of about 225-250 grams. The purpose of this test was to ascertain the dose response of the delivery agent compound. Glucose reduction was determined as set fortb in connection with the data in Table 1.
Table 2: Dose Response of Delivery Aunt Compounds 2, 5, 6 and 8 Delivery Agent Dose Response:
Insulin 0.5 mg/kg Delivery Agent Amount of Delivery % Glucose Compound Agent Compound (mg/kg) Reduction 2 25 -10.0 50 -13.5 5 100 -18.2 6 100 -19.2 6 50 -15.8 8 50 -30.5 8 25 -9.7 SUBSTITUTE SHEET (RULE 26) Insulin Titrations were performed with Delivery Agent 29 in order to gauge the effect of varying dosages of insulin. The results are shown below in Table 3:
Table 3: Insulin Dose Titrations of Delivery A ent Compounds Insulin Titrations:
Delivery Agent 200 mg/kg Delivery Dose of Insulin % Glucose Com Agent (mg/kg) Reduction ound 29 0.50 -30.8 29 0.25 -31.4 29 0.00 -6.8 Example 68 -- Oral and Intracolonic delivery of Heparin to Male S ra ue-Dawle Rats [163] Oral gavage and/or intracoloo.ic (IC) dosing solutions containing delivery agent compound and heparin sodium USP were prepared in 25% aqueous propylene glycol.
Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt with one equivalent of sodium hydroxide. The delivery agent compound and heparin (about 166-182 IU/mg) were mixed by vortex as dry powders. This dry mixture was dissolved in 25% v/v aqueous propylene glycol, vortexed, and placed in a sonicator (about 37 C). The pH
was adjusted to about 7 (6.5 - 8.5) with aqueous NaOH (2N). The dosing solution was sonicated to produce a clear solution. The final volume was adjusted to about 3.0 ml.
The final delivery agent compound dose, and heparin dose are listed in Table 4.
[164] Male Sprague-Dawley rats weighing between about 275-350 g were fasted for 24 hours and anesthetized with ketamine hydrochloride (88 mg/kg) intramuscularly immediately prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals were administered one of the dosing solutions. For oral gavage dosing, an 1 I cm Rusch 8 French catheter was adapted to a I ml syringe with a pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which was then wiped dry. The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger, SUBSTITUTE SHEET (RULE 26) [165] For intracolonic (IC) dosing, a 7.5 cm, 8 French Rusch catheter was adapted to a I
ml syringe with a pipette tip. The dosing catheter was inserted into the colon through the anus until the tube was no longer visible. The dosing solution was expressed slowly into the colon by pressing the syringe plunger.
[166] Citrated blood samples were collected by cardiac puncture following the administration of ketamine (88 mg/kg), typically at 0.25, 0.5, 1.0 and 1.5 hours after dosing.
Heparin absorption was verified by an increase in clotting time measured by the activated partial thromboplastin time (APTT) according to the method of Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods, Philadelphia, PA, W.B. Saunders (1979), which is hereby incorporated by zeference. Previous studies indicated baseline values of about 20 seconds.
Results from the animals in each group were averaged for each time points and the highest of these averages (i.e. mean peak APTT) is reported.
[167] The oral and intracolonic APTT results and plasma heparin concentrations for delivery agents 1, 2, 6, 7, 11, 35 and 59 are shown in Figure 1-3. The following delivery agents were administered as positive controls:
Delivery Agent Structure Notation in Figure o H D.A. õAõ
N
~ OH
H D.A. "Jil """'j OH
OH D.A. ,Wr N N OH
H
SUBSTITUTE SHEET (RULE 26) D.A."L"
O O
N N OH
H
OH D.A. Mõ
I !I
N
H
D.A. "N"
OH
OH O ~
I
~ 0 N
H
Table 4- Intracolonic delivery of Heparin Intracolonic:
Delivery Agent 50 mg/kg; USP Heparin 25 mg/kg Delivery APTT Tmax Agent (seconds) (Minutes) 11 300.0 30.0 35 100.0 30.0 SUBSTITUTE SHEET (RULE 26) Table 5- Oral delivery of Heparin Oral:
Delivery Agent 200 mg/kg; Heparin 80 mg/kg Delivery Agent [Plasma Heparin] Tmax (U/mL) (Minutes) 2 0.5 45 6 0.2 15 1 7 0.7 60 Example 69 -- Oral Delivery of Recombinant Human Growth Hormone (rhGH) to Male Sprnue-Dawley Rats [168] Oral gavage dosing solutions of delivery agent compound and rhGH in phosphate buffer were prepared by mixing. A solution of the delivery agent compound was made either with the sodium salt of the delivery agent compound or by converting the free acid to its sodium salt. A solution of the delivery agent compound was prepared in phosphate buffer and stirred, adding one equivalent of sodium hydroxide (1.0 N) when making the sodium salt.
The final dosing solutions were prepared by mixing the delivery agent compound solution with an rhGH
stock solution (15 mg rhGH/ml glycine and 3.39 mg dibasic sodium phosphate, then diluted with 2% glycerol) with rhGH obtained from Eli Lilly and diluting to the desired volume (usually 3.0 ml). The pH was adjusted, if necessary, to between about 7 and 8.8. The delivery agent compounds and rhGH dose amounts are listed in Table 6.
[169] Male Sprague-Dawley rats weighing about 200-250 g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 xng/kg) 15 minutes prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals was administered one of the dosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with the dosing solution by drawing the solution through the catheter, which was then wiped dry. The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger.
SUBSTITUTE SHEET (RULE 26) [170] Blood samples were collected serially from the tall arterv at time = 15, 30, 45, 60 and 90 minutes. The five samples from each time period were pooled. Serum rhGH
concentrations were quantified by an rhGH immunoassay test kit. Previous studies indicated baseline values of about zero. The maximum concentration at Tmax for each group tested with rhGH is listed.
Table 6- Oral delivery of rhGH
Oral:
Delivery Agent 200 mg/kg; rhGH 3 mg/kg Delivery Serum Level Tmax Agent (ng/rnL) (Minutes) [171] Average serum hGH concentrations over 90 minutes for delivery agent 11 is shown in Figures 4 and 5. The following delivery agents were administered as positive controls:
Delivery Agent Structure Notation in Figure D.A. ~'N
OH
OH O ~
~
\ 0 N
H
0 D.A. "oõ
oH
HO
SUBSTITUTE SHEET (RULE 26) HO ` D. A. "P"
OH
Example 70 -- Oral Delivery of Luteinizing Hormone-Releasing Hormone LHRH to Male Sprague-Dawley Rats [172] Oral gavage dosing solutions of delivery agent compound and LHRH in phosphate buffer were prepared by mixing. A solution of the delivery agent compound was made either with the sodium salt of the delivery agent compound or by converting the free acid to its sodium salt. A solution of the delivery agent compound was prepared in phosphate buffer and stirred, adding one equivalent of sodium hydroxide (1.0 N) when making the sodium salt.
The final dosing solutions were prepared by mixing the delivery agent compound solution with a LHRH stock solution (2.75 ml with a concentration of 20 mg/ml in aqueous solution). The pH
was adjusted, if necessary, to between about 7 and 8.8. The delivery agent compounds and LHRH dose amounts are listed in Table 7.
[173] Male Sprague-Dawley rats weighing between about 250-300 g were fasted foz 24 hours. A dosing group of five animals was administered one of the dosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with the dosing solution by drawing the solution through the catheter, which was then wiped dry.
The catheter was placed down the esophagus leaving 1 em of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger.
[174] Blood samples were collected through retroorbital bleeding of approximately 0.4 ml of blood volume using EDTA tubes at time = 0 (pre-dose), 2, 10, 15 and 30 minutes. The five samples from each time periad were pooled. Previous studies indicated baseline values of about zero. The maximum absorption at the Tmax is reported below in Table 7.
Results for delivery agents 5, 6, 7 and 58 are also shown in Figure 9. As controls, 4-(3-methyl phenoxy) butyric acid (D.A. "B"), the mesylate salt of (4-(8-(2-hydroxyphenoxy)octyl) morpholine (D.A.
SUBSTITUTE SHEET (RULE 26) "C"), 4-(4-(2-hydroxyphcnoxy)butyl) morpholine (D.A. "D"), and 4-(6-(2-hydroxyphenoxy)hexyl) morpholine (D.A. "E") were also administered according to the same protocol and their results are also shown in Figure 6.
Table 7- Oral delivery of LHRH
Oral Absorption of LHRH in Rats Delivery Agent: 200 mglkg; LHRH: 1mg/kg Plasma LHRII
Delivery Tn1ax Agent concentration (Minutes) (ng/mL) Example 71 -- Oral Delivery of Cas ofun in Acetate to Male S ra ue-Dawie Rats [175] Oral gavage dosing solutions of delivery agent compound and caspofungin acetate (Merck & Co., Whitehouse Station, NJ) in phosphate buffer were prepared by mixing. A
solution of the delivery agent compound was made either with the sodium salt of the delivery agent compound or by converting the free acid to its sodium salt. A solution of the delivery agent compound was prepared in phosphate buffer and stirred, adding one equivalent of sodium hydroxide (1.0 N) when making the sodium salt. The final dosing solutions were prepared by mixing the delivery agent compound solution with a caspofungin acetate stock solution (2.5 ml with a concentration of 100 mg/ml in aqueous solution). The pH was adjusted, if necessary, to between about 7 and 8.8. The delivery agent compounds and caspofungin acetate dose amounts are listed in Table 8.
[176] Male Sprague-Dawley rats weighing between about 250-300 g were fasted for 24 hours. A dosing group of five animals was administered one of the dosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with the dosing solution by drawing the solution through the catheter, which was 'tlien wiped dry.
SUBSTITUTE SHEET (RULE 26) The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger.
[177] Blood samples were collected through retroorbital bleeding at time - 0 (pre-dose), 15, 30, 60, 240, and 480 minutes. The five samples from each time period were pooled.
Previous studies indicated baseline values of about zero. The maximum concentration at the Tmax is reported.
Table 8- Oral delivery of caspofungin acetate Oral caspofungin acetate:
Delivery Agent 200 mglkg; caspofungin acetate: 25 mglk plasma caspofungin Delivery Tmax acetate rnutes Agent concentration ~ ~
(ng/mL) [178] The results for delivery agent 14 is also shown in Figure 10. The delivery agents N-6-2-hydroxy-5-chlorobenzoyl amino hexanoic acid (D.A. "F"), 6-(2-methylformylphenoxy) hexanoic acid (D.A. "E"), 4-(3-methylphenoxy) butyric acid (D.A. "B"), 3-(3-fluoro) propionic acid (D.A. "H"), and 5-phenyl pentanoic acid (D.A. "I") were also administered as controls according to the same protocol and their results are shown in Figure 7.
[179] The above-mentioned patents, applications, test methods, and publications are hereby incorporated by reference in their entirety.
[180] The present invention has been described in details with particular reference to the preferred embodiments thereof, but it will be understood that many variations and modifications of the present invention suggest themselves to those skilled in the art in light of the above detailed description. All such obvious variations and modifications can be affected without departing the spirit and scope of the appended claims of the present invention.
SUBSTITUTE SHEET (RULE 26)
methylene chloride. The mixture was cooled with an external ice bath. Boron tribromide solution (25 ml of a 1 M solution in methylene chloride, 25 mmol) was added and the external ice bath removed. After 10 minutes the reaction was heated to reflux for 10 minutes and allowed to cool to room temperature. Boron tribromide solution (25 ml of a 1 M
solution in methylene chloride, 25 mmol) was added and the reaction allowed to mix at room temperature for 15 minutes. The reaction was cooled with an external ice bath and then quenched with 75 mL of water. This mixture was allowed to stir at room temperature for 18 hours. The layers were separated and the aqueous layer was extracted with methylene chloride (2 X 40 mL). The organic layers were combined and washed with water (40 mL) and then brine solution (40 mL).
The organic layer was dried over sodium sulfate, filtered, and then the solvent removed under reduced pressure. The residue was dissolved in aqueous 1 N sodium hydroxide (25 mL) and SUBSTITUTE SHEET (RULE 26) diluted with 100 mL water. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 14 days. The brown solid was collected by suction filtration. Solid was dissolved in aqueous 1 N sodium hydroxide solution (25 mL) and diluted with 75 mL water.
The solution was acidified to pH 8 with aqueous 1 N hydrochloric acid and cooled to 4 C. The pH was the lowered slowly by the addition of 2-3 drops of aqueous 1 N
hydrochloric acid two times a day for 21 days at 4 C. At end of time period 5 mL of aqueous 1 N
hydrochloric acid was added to ensure pH 1 and solution allowed to set for 18 hours at 4 C. The off-white product and one solid brown chunk were collected by suction filtration and the brown chunk removed with forceps. The product (2.54 g, 62%) was isolated as an off-white solid, mp 49-50 C. Found:
C: 62.52 %, H: 7.35 % S: 101.91 %; C14H2003S requires C: 62.47 %, H: 7.52 %, S: 11.91 %; IH
NMR (d6-DMSO): 612.0, broad s, 1H (COOH); 59.70, s, 1H (Ar-OH); S 7.16, dd, 1H
(aryl H); 8 7.01, dt, 1H (aryl H); S 6.80, dd, 1H (aryl H); S 6.77, dt, 1H (aryl H); $
2.82, t, 2H (CH2 (L to S);
$ 2.18, t, 2H (CH2 a to COOH); S 1.6-1.2, multiplet, l OH (rest of CH2`s).
Example 6-- Preparation of 6- 2 5-Dimeth 1- hen lsulfan 1-hexanoic acid (Compound [99] To a 500 mL flask, equipped with a magnetic stir bar, was added ethyl 6-bromo-hexanoate (5.25 mL, 30 mmol), 2,5-dimethylbenzen.ethiol (4.0 mL, 30 mmol), and 100 mL ethyl alcohol. The reaction vessel was cooled with an external ice bath while potassium hydroxide (5.32 g, 95 ininol) was added. The external ice bath was removed and the reaction was allowed to stir at room temperature for 18 hours under a nitrogen atmosphere. Water (100 mL) was added and the reaction was allowed to mix at room temperature for an additional 18 hours. Ethyl alcohol was removed under reduced pressure. The remaining solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours. The product (6.39 g, 86%) was isolated by filtration as a white solid, mp 61-62 C. Found: C: 66.80 %, H:
8.00 % S: 12.68 %;
C14H2002S requires C: 66.63 %, H: 7.99 %, S: 12.71 %; IH NMR (d6-DMSO): (COOH, not visible due to water in sample); 6 7.08, s, 1H (aryl H); S 7.06, d, IH (aryl H); S 6.88, d, 1H (aryl H); 6 2.90, t, 2H (CH2 a to S); 6 2.26, s, 3H (aryl-CH3); S 2.21, s, 3H (Aryl-CH3); S 2.19, t, 2H
(CH2 a to COOH); d 1.65-1.35, multiplet, 6H (rest of CH2`s).
SUBSTITUTE SHEET (RULE 26) Example 7 -- Preparation 4- 2 5-Dirneth 1- hen 1sulfan 1-bu ric acid Com ound [100] Prepared analogously to Compound 6 with ethyl 4-bromobutyrate (2.88 mL, mmol), 2,5-dimethylbenzenethiol (2.0 mL, 15 mmol), potassium hydroxide (2.54 g, 45 mmol), and 100 mL ethyl alcohol. The product (2.87 g, 87%) isolated as an off-white solid, mp 61-62 C. Found: C. 64.18 %, H: 7.26 % S. 14.39 %; C12H1602S requires C: 64.06 %, H: 7.20 %, S:
14.25 %; 1 H NMR (d6-DMSO): $ 12.14, s, 1 H(COOH); 6 7.13, s, 1 H(aryl H); 6 7.08, d, 1 H
(aryl H); S 7.06, d, 1H (aryl H); 6 2.94, t, 2H (CH2 (I to S); 6 23 8, t, 2H
(CH2 a to COOH); 6 2.26, s, 3H (aryl-CH3); 6 2.22, s, 3H (Aryl-CH3); 6 1.78, quintuplet, 2H
(other CH2`s).
Example 8 -- Preparation of 10- 2-H drox - hen lsulfan 1-decanoic acid (Compound S:
[101] Prepared analogously to Compound 3 with 2-hydroxybenzenethiol (1.5 mL, mmol), ethyl 10-bromodecanoate (4.16 g, 15 mmol), potassium hydroxide (2.49 g, 44 mmol), 10 mL ethyl alcohol, aqueous I N sodium hydroxide solution (4 mL), and water (15 mL). Product was further purified by recrystallization from hexanes twice. The product (1.81 g, 41 %) was isolated as an off-white solid, mp 58-59 C. Found: C: 64.27 %, H: 8.07 % S:
10.61 %;
C16H2403S requires C: 64.32 %, H: 8.19 %, S: 10.73 %; 1H NMR (d6-DMSO): b 12.00, broad s, 1H (COOH); 6 9.70, broad s, 1H (Aryl-OH); 8 7.16, d, 1H (aryl H); 6 7.00, t, 1H (aryl H); S 6.77, multiplet, 2H (other aryl H's); 6 2.82, t, 2H (CH2 a to S); 6 2.18, t, 2H (CH2 a to COOH); 6 1.60-1.15, multiplet, 14H (rest of CHZ`s).
Example 9 -- Preparation of 3- 2 5-Dimeth l- hen lsuMfan 1- ro ionic acid (Compound 9):
[102] Prepared analogously to Compound 6 with 2,5-dimethylbenzenethiol (3.0 mL, 22 mmol), ethyl 3-bromopropionate (4.04 g, 22 mmol), potassium hydroxide (3.49 g, 62 mmol), 100 mL ethyl alcohol and water (20 mL). The product (2.57 g, 55%) was isolated as a white solid, mp 100-102 C. Found: C: 62.83 %, H: 6.76 % S: 15.29 %; CI 1H1402S requires C:
62.71 %, H:
6.72 %, S: 15.22 %; IH NMR (d6-DMSO): 6 12.40, broad s, 1H (COOH); 6 7.12, s, 1H (aryl H); S 7.08, d, 1H (aryl H); 8 6.92, d, 1H (aryl H); S 3.09, t, 2H (CH2 a to S); 6 2.53, t, 2H (CH2 a to COOH); 6 2.27, s, 3H (aryl-CH3); 6 2.22, s, 3H (Aryl-CH3).
SUBSTITUTE SHEET (RULE 26) Example 10 -- Preparation of 8-(4-Methoxy-phenylsulfanyl)-octanoic acid (Compound 10);
[103] Prepared analogously to Compound 6 with 4-methoxybenzenethiol (4.0 mL, mmol), ethyl 8-bromooctanoate (8.21 g, 33 mmol), potassium hydroxide (5.57 g, 99 mmol), lOOmL ethyl alcohol and water (65 mL). The product (8.76 g, 95%) was isolated as an off-white solid, mp 66-68 C. Found: C: 63.29 %, H: 7.72 % S: 11.27 %; C15H2203S requires C. 63.64 %, H: 7.86 %, S: 11.33%; 1H NMR (d6-DMSO): b 7.30, d, 2H (aryl H's); 6 6.90, d, 2H (aryl H's);
S 3.74, s, 3H (OCH3); S 2.83, t, 2H (CH2 a to S); S 2.17, t, 2H (CH2 a to COOH); 5 1.60-1.20, multiplet, 10H (rest of CH2`s).
Example 11 -- Preparation of 8-(4-Hydroxy-phenylsulfanyl)-octanoic acid (Compound 11):
[104] To a 500 mL flask, equipped with a magnetic stir bar and a 60-mL
addition funnel, was added 4-hydroxybenzenethiol (5.22 g, 41 mmol), potassium carbonate (7.03 g, 51 mmol), and 100 mL ethyl alcohol. The reaction vessel was cooled with an external ice bath.
The addition fuzuiel was charged with ethyl 8 -bromoo etanoate (10.41 g, 41 mmol) and 55 mL
ethyl alcohol. This was then added drop-wise to the reaction vessel over 1 hour. The reaction was allowed to warm to room temperature and stirred for 18 hours under a nitrogen atmosphere.
Ethyl alcohol was removed under reduced pressure. The residue was dissolved in 10 mL ethyl alcohol and 80 mL of aqueous 1 N sodium hydroxide solution and allowed to stir at room temperature for 18 hours. Solution was acidified to pH 1 with aqueous 1 N
bydrochloric acid and cooled to 4 C for 18 hours. The product (10.20 g, 92%) was isolated by filtration as an off-white solid, mp 94-95 C. Found: C: 61.79 %, H: 7.55 % S: 11.50 %; C14H2003S
requires C:
62.07 %, H: 7.55 %, S: 121.84 %; 1H NMR (d6-DMSO): cS 12.00, s, 1H (COOH); 6 10.55, s, 1H
(Aryl-OH); S 7.20, d, 2H (aryl H's); 6 6.72, d, 2H (aryl H's); S 2.77, t, 2H
(CH2 a to S); S 2.18, t, 2H (CH2 a to COOH); S 1.55-1.20, multiplet, lOH (rest of CH2`s).
Example 12 -- Preparation of 4-(2-H_ydroxy-phenylsulfanyl)-butyric acid (Compound 12):
[105] To a 250 mL round bottom was added 2-hydroxybenzenthiol (1.5 mL, 15 mmol), ethyl 4-bromobutyrate (2.14 mL, 15 mmol) and 100 mL ethyl alcohol. The mixture was cooled with an external ice bath. Potassium hydroxide (0.85 g, 15 mmol) was added and the mixture was allowed to warrn to room temperature and stirred for 18 hours. Aqueous 1 N
sodium hydroxide solution (80 mL) was added and the reaction allowed to mix at room temperature for SUBSTITUTE SHEET (RULE 26) 18 hours. Ethyl alcohol was removed under reduced pressure and the residue was acidifzed with aqueous 1 N hydrochloric acid solution to pH 7 and cooled to 4 C. The pH was lowered slowly by the addition of aqueous I N hydrochloric acid solution (1-3 drops a day for 60 days.) During this period, the reddish oily that initially forms was removed via pipette upon the initial formation of a white precipitate. The product (1.98 g, 62%) was isolated by suction filtration as an off-white solid, mp 77-78 C. Found: C: 56.54 %, H: 5.84 % S: 14.98 %;
C10Haz03S requires C: 56.58 %, H: 5.70 %, S: 15.11 %; 1H NMR (d6-DMSO): 612.1, broad s, IH
(COOH); 59.75, s, IH (Ar-OH); 6 7.19, dd, iH (aryl H); 8 7.02, dt, 1H (aryl H); 6 6.78, muitiplet, 2H (aryl H's); 6 2.85, t, 2H (CH2 a to S); S 2.34, t, 2H (CH2 a to COOH); S 1.72, quintuplet, 2H (other CH2).
Example 13 -- Pre aration of 4-Methox - hen lsulfan 1-acetic acid Com ound 13 :
[106] To a mini-block tube was added 4-methoxybenzenthiol (2.50 mL, 20 mmol), ethyl bromoacetate (2.28 mL, 20 mmol), potassium hydroxide (2.33 g, 42 mmol) and 30 mL ethyl alcohol. The mixture was stirred under nitrogen for 18 hours. 5 mL of water and 5 mL of aqueous 1 N sodium hydroxide solution were added. The reaction mixture was heated (84 C) for 3 hours under atmospheric conditions to remove a majority of the ethyl alcohol. The mixture was cooled to room temperature and acidified with aqueous 1 N hydrochloric acid to pH 1 and allowed to stir at room temperature for 18 hours. The product (3.22 g, 80%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 512.66, broad s, 1H
(COOH); 6 7.33, multiplet, 2H (aryl H); b 6.89, multiplet, 2H (aryl H); 8 3.71, s, 3H (-OCH3);
d 3.60, s, 2H (CH2).
Example 14 -- Preparation of 5- 4-Methox - hen lsulfan 1- entanoic acid Com ound 14 :
[107] Prepared analogously to Compound 13 with 4-methoxybenzenthiol (2.00 mL, mmol), ethyl 5-bromopentanoate (2.57 mL, 16 mmol), potassium hydroxide (1.98 g, 35 mmol) and 30 mL ethyl alcohol. The product (3.22 g, 80%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 511.95, broad s, 1H (COOH); S 7.26, multiplet, 2H
(aryl H); 6 6.85, multiplet, 2H (aryl H); 6 3.69, s, 3H (-OCH3); d 2.78, t, 2H (CH2 a to S); 6 2.15, t, 2H (CH2 a to COOH); fi 1.60-1.40, multiplet, 4H (rest of CHZ`s).
SUBSTITUTE SHEET (RULE 26) Example 15 -- Preparation of 6- 4-Methox - hen lsulfan 1-hexanoic acid (Compound 15 :
[108] Prepared analogously to Compound 13 with 4-methoxybenzenthiol (2.00 mL, mmol), ethyl 6-bromohexanoate (2.89 mL, 16 mmol), potassium hydroxide (1.98 g, 35 mmol) and 30 mL ethyl alcohol. The product (3.34 g, 80%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): (COOH); S 7.40, multiplet, 2H (aryl H); 6 7.00, multiplet, 2H (aryl H); S 3.83, s, 3H (-OCH3); 6 2.91, t, 2H (CH2 a to S); 6 2.26, t, 2H (CH2 a to COOH); S 1.65-1.40, multiplet, 6H (rest of CH2`s).
Example 16 -- Preparation of 7- 2-Methox - hen yisulfan 1-he tanoic acid Com ound 16 :
[109] Prepared analogously to Compound 6 with 2-methoxybenzenethiol (1.4 mL, mmol), ethyl 7-bromoheptanoate (2.2 mL, 11 mmol), 30 mL ethyl alcohol, potassium hydroxide (1.9 g, 34 mmol), and 25 mL water. Crude product was further purified by dissolving in 10 mL
of aqueous 1 N sodium hydroxide solution and 100 mL of water and then acidifying solution to pH 1 with aqueous I N hydrochloric acid. Product (2.2 g, 73%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): 6 12.0, broad s, 1H (COOH); 6 7.19, dd, 1H
(aryl H); 6 7.13, dt, 1 H (aryl H); 6 6.9, multiplet, 2H (aryl H); S 3. 8, s, 3H (OCH3); 6 2.8, t, 2H (CHZ a to S);
b 2.2, 2H (CH2 a to COOH); 6 1.6-1.2, complex, 8H (rest of CH2's).
Example 17 -- Preparation of 4- 4-Metb.ox - henvlsulfan 1-bu ric acid Com ound 17):
[110] Prepared analogously to Compound 13 with 4-methoxybenzenthiol (2.00 mL, mmol), ethyl 4-bromobutyrate (2.33 mL, 16 mmol), potassium hydroxide (1.96 g, 35 mmol) and 30 mL ethyl alcohol. The crude product was dissolved in aqueous I N sodium hydroxide solution (10 mL) and 10 mL water. The cloudy aqueous layer was decanted off from the insoluble viscous yellow-brown oil and was then acidified to pH 1 with aqueous I N
hydrochloric acid. The product (2.72 g, 74%) was isolated by filtration as a white solid. 1H
NMR (d6-DMSO): 511.95, broad s, 1H S 12.08, s, IH (COOH); S 7.31, multiplet, 2H (aryl H); 6 6.91, multiplet, 2H (aryl H); S 3.74, s, 3H (-OCH3); 6 2.84, t, 2H (CH2 a to S); 8 2.33, t, 2H (CH2 a to COOH); S 1.70, p, 2H (last CH2).
SUBSTITUTE SHEET (RULE 26) Example 18 -- Preparation of 3- 4-Methox - hen lsulfan 1- ro ionic acid (Compound 18 :
[111] Prepared analogously to Compound 17 with 4-methoxybenzenthiol (2.50 mL, mmol), ethyl 3-bromopropanoate (2.61 mL, 20 mmol), potassium hydroxide (2.39 g, 42 mmol) and 30 mL ethyl alcohol. The product (2.30 g, 53%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 8 12.29, s, 1H (COOH); 6 7.33, multiplet, 2H (aryl H); 6 6.92, multiplet, 2H (aryl H); S 3.74, s, 3H (-OCH3); 6 2.99, t, 2H (CH2 a to S); S
2.44, t, 2H (CH2 a to COOH).
19 :
Example 19 -- Preparation of 5- 2-Methox - hen lsulfan 1- entanoic acid (Compound [112] Prepared analogously to Compound 6 with 2-methoxybenzenethiol (1.5 mL, 12.5 mmol), ethyl 5-bromovalerate (2.0 mL, 12.5 mmol), 25 mL ethyl alcohol, potassium hydroxide (2.0 g, 37 mmol), and 15 mL water. Product (2.6 g, 87%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.0, broad s, 1 H(COOH); S 7.2, dd, 1 H(aryl H); 7.14, dt, 1H (aryl H); 6 6.9, 2H (aryl H); 6 3.8, s, 3H (OCH3); S 2.85, t, 2H (CH2 a to S); S 2.2, t, 2H (CH2 a to COOH); S 1.7-1.5, complex, 4H (rest of CH2's).
Example 20 -- Preparation of 10- 3-Methox - hen lsulfan yl -decanoic acid (Compound 20 :
[113] Prepared analogously to Compound 6 with 3-methoxybenzenethiol(1.2 mL, 9.7 mmol), ethyl 10-bromodecanoate (2.3 mL, 9.7 mmol), 45 mL ethyl alcohol, potassium hydroxide (1.6 g, 29 mmol), and 15 mL water. Product (2.6 g, 88%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.0, broad s, IH (COOH); S 7.2, t, 1H (aryl H); 8 6.8, multiplet, 2H (aryl H); 6 6.7, dd, 1H (aryl H); 8 3.7, s, 3H (OCH3); d 29, t, 2H (CH2 a to S); b 2.15, t, 2H (CH2 a to COOH); S 1.6-1.1, complex, 14H (rest of CHZ's).
Example 21 -- Preparation of 6- 3-Methox - hen lsulfan 1-hexanoic acid (Compound 21):
[114] Prepared analogously to Compound 6 with 3-methoxybenzenethiol (2.0 mL, mmol), ethyl 6-bromohexanoate (2.9 mL, 16 mmol), 35 mL ethyl alcohol, potassium hydroxide (2.7 g, 49 mmol), and 20 mL water. The product (3.7 g, 89%) was isolated as a white powder by filtration. 11I NMR (d6-DMSO): S 7.19, t, 1H (aryl H); 8 6.83, multiplet, 2H
(aryl H); S 6.71, dd, 1H (aryl H); b 3.72, s, 3H (OCH3); S 2.92, t, 2H (CH2 a to S); 6 2.15, t, 2H (CH2 a to COOH); 8 1.6-1.3, complex, GH (rest of CHZ's).
SUBSTITUTE SHEET (RULE 26) Example 22 -- Preparation of $- 3-Methox - hen lsulfan 1-hexanoic acid (Compound 22):
[115] Prepared analogously to Compound 6 with 3-methoxybenzenethiol (1.5 mL, mmol), ethyl 8-bromooctanoate (2.6 mL, 12 mmol), 30 mL ethyl alcohol, potassium hydroxide (2.0 g, 36 mmol), and 15 mL water. Ethyl alcohol was distilled at atmospheric pressure. The crude product was further purified by dissolving in 10 mL aqueous I N sodium hydroxide solution and 100 mL of water. The solution was acidified to pH 1 with aqueous I N
hydrochloric acid. The product (2.9 g, 93%) was isolated as a white solid by filtration. 1H NMR
(d6-DMSO): S 12.0, broad s, 1H (COOH); 6 7.2, t, IH (aryl H); S 6.83, multiplet, 2H (aryl H); 6 6.71, dd, 1H (aryl H); $ 3.72, s, 3H (OCH3); 8 2.93, t, 2H (CH2 a to S); S
2.16, t, 2H (CH2 a to COOH); S 1.6-1.2, complex, lOH (rest of CH2's).
Example 23 -- Pre aration of 3-Chloro- hen lsulfan 1-acetic acid (Compound 23 :
[116] Prepared analogously to Compound 13 with 3-chlorobenzenethiol (2.00 mL, mmol), ethyl bromoacetate (1.91 mL, 17 mmol), potassium hydroxide (3.04 g, 54 mmol) and 40 mL ethyl alcohol. Hydrolysis step used 20 mL water and 10 mL of aqueous 1 N
sodium hydroxide solution and was heated to 55 C for 5 hours. The product (3.11 g, 89%) was isolated by filtration as a white solid. 1H NMR (d6-DMSO): 512.85, broad s, 1H (COOH);
b 7.39, t, 1H
(aryl H); S 7.33, t, 1H (aryl H); 6 7.28, dt, 1H (aryl H); b 7.24, dt, 1H
(aryl H); 8 3.88, s, 2H
(CH2).
Example 24 -- Preparation of 5- 3-Chloro- hen Isulfan I- entanoic acid Com ound 24):
[117] Prepared analogously to Compound 23 with 3-chlorobenzenthiol (2.00 mL, mmol), ethyl 5-bromopentanoate (2.72 mL, 17 mmol), potassium hydroxide (3.10 g, 55 mmol) and 30 mL ethyl alcohol. The product (3.73 g, 88%) was isolated by filtration as a white solid.
IH NMR (d6-DMSO): 612.85, broad s, 1H (COOH); S 7.35, t, 1H (aryl H); 6 7.32, t, 1H (aryl H); 6 7.26, dt, 1H (aryl H); 6 7.21, dt, 1H (aryl H); 8 3.01, t, 2H (CH2 ca to S); b 2.24, t, 2H (CH2 a to COOH); 6 1.7-1.5, complex, 4H (rest of CH2's).
Example 25 -- Preparation of 5- 2-Chloro- hen lsulfan 1- entanoic acid (Compound 25):
[118] Prepared analogously to Compound 23 with 2-chlorobenzenthiol (2.00 mL, mmol), ethyl 5-bromopentanoate (2.80 mL, 1$ mmol), potassium hydroxide (3.10 g, 55 mmol) SUBSTITUTE SHEET (RULE 26) and 30 mL ethyl alcohol. The product (3.86 g, 89%) was isolated by filtration as a white solid.
1H NMR (d6-DMSO): 512.03, s, lH (COOH); 6 7.44, dd, 1H (aryl H); 6 7.38, dd, 1H (aryl H); 6 7.33, dt, 1H (aryl H); d 7.18, dt, 1H (aryl H); 8 3.00, t, 2H (CH2 a to S); S
2.26, t, 2H (CH2 a to COOH); S 1.7-1.6, complex, 4H (rest of CH2's).
26 :
Exam le 26 -- Preparation of 6- 2-Chloro- hen lsulfan 1-hexanoic acid (Compound [119] Prepared analogously to Compound 23 with 2-chlorobenzenthiol(2.00 mL, 18 inmol), ethyl5-brornopentanoate (3.14 mL, 18 mmol), potassium hydroxide (3.04 g, 54 mmol) and 30 mL ethyl alcohol. The product (4.25 g, 93%) was isolated by filtration as an off-white solid. 1H NMR (d6-DMSO): 611.99, s, 1H (COOH); 6 7.44, dd, 1H (aryl H); 6 7.37, dd, 1H (aryl H); 6 7.33, dt, 1H (aryl H); 6 7.17, dt. 1H (aryl H); 6 2.99, t, 2H (CH2 a to S); 6 2.20, t, 2H (CH2 a to COOH); S 1.7-1.3, complex, 6H (rest of CH2's).
Example 27 -- Preparation of 4- 3-Methox - hen lsulfan 1-bu ric acid (Compound 27):
[120] Prepared analogously to Compound 6 with 3-methoxybenzenethiol (1.7 mL, mmol), ethyl 4-bromobutyrate (1.9 mL, 13 mmol), 25 mL ethyl alcohol, and potassium hydroxide (2.5 g, 44 mmol). Reaction was allowed to stir under nitrogen atmosphere for 10 days. Water (15 mL) was added and the reaction was allowed to mix for 5 hours.
Ethyl alcohol was distilled off under atmospheric pressure. The residual was diluted with water (10 mL) was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours. The crude product, isolated by filtration, was further purified by dissolving in 10 mL
aqueous 1 N sodium hydroxide solution and 100 mL of water. The solution was then acidified to pH
1 with aqueous I N hydrochloric acid and crude product collected by filtration. The crude product was then dissolved in 10 mL aqueous 1 N sodium hydroxide solution and 100 mL of water.
The solution was then slowly acidified step wise to pH 7, pH 6, pH 5 and finally to pH 1 by the addition of aqueous 1 N hydrochloric acid. At each step the small amount of yellow oil that precipitated was removed via pipette. Product (1.6 g, 52%) was isolated as off=whi'te solid by filtration. 1 H NMR
(d6-DMSO): S 12.1, broad s,1 IH (COOH)6 7.17, t, 1 H(aryl H); S 6.83, multiplet, 2H (aryl H); S
6.7, dd,1H (aryl H); 6 3.7, s, 3H (OCH3); 6 2.9, t, 2H (CH2 a to S); 2.3, t, 2H (CH2 a to COOH);
S 1.73, quintet, 2H (remaining CH2).
SUBSTITUTE SHEET (RULE 26) Exam le 28 -- Preparation of 2-Chloro- hen 1sulfan 1-acetic acid (Compound 28):
[121] To a mini-tube equipped with a inagnetic stir bar, was added 2-chlorobenzene thiol (1.0 mL, 8.8 mmol), ethyl bromoacetate (0.98 mL, 8.8 mmol), and 35 mL
ethyl alcohol.
Potassium hydroxide (1.5 g, 24 mmol) was added at room temperature. Reaction was stirred at room temperature under nitrogen atmosphere for 18 hours. Water (20 mL) was added and the reaction stirred for 3 hours. Ethyl alcohol was distilled at atmospheric pressure and the residual was diluted with 100 mL of water. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 2 hours. The product (1.2 g, 61 %) was isolated as white powder by filtration. 1H NMR (d6-DMSO): 6 12.9, broad s, 1H (COOH); 6 7.4, d, 1H (aryl H);
b 7.3, dd, 2H (aryl H); 6 7.15, multiplet, 1H (aryl H); 6 3.85, s, 2H (CH2).
Exam le 29 -- Preparation of a- 3-Chloro- hen lsulfan 1-bu ric acid Com ound 29):
[122] Prepared analogously to Compound 23 with 3-chlorobenzenthiol (2.00 mL, mmol), ethyl 4-bromobutyrate (2.47 mL, 17 mmol), potassium hydroxide (3.03 g, 54 mmol) and 30 mL ethyl alcohol. The crude product was further purified by dissolving in 20 mL of aqueous I N sodium hydroxide solution and 30 mL water. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid. The product (2.99 g, 75%) was isolated by filtration as a brownish solid. 1H NMR (d6-DMSO): 812.85, broad s, 1H (COOH); 6 7.37, t, 1H
(aryl H); 6 7.32, t, 1H (aryl H); 6 7.27, dt, IH (aryl H); S 7.22, dt, 1H (aryl H); 6 3.01, t, 2H (CH2 a to S); b 2.35, t, 2H (CH2 a to COOH); 6 1.77, pentet, 2H (other CH2's).
Example 30 -- Preparation of 8- 2-Chloro- hen lsulfan 1-octanoic acid (Compound 30 :
[123] To a mini-tube equipped with a magnetic stir bar, was added 2-chlorobenzene thiol (1.0 mL, 8.2 mmol), ethyl 8-bromooctanoate (1.8 mL, 8.2 mmol), and 45 mL
ethyl alcohol.
Potassium hydroxide (1.5 g, 26 mmol) was added at room temperature and the reaction was allowed to stir at room temperature for 1 hr under a nitrogen atmosphere.
Water (10 mL) was added and the stirring continued for 3 hours. The reaction was heated to 45 C
for 0.5 hr, cooled to room temperature and stirred for an additional 96 hours. Solvent was removed under reduced pressure and the resulting solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 45 min. Product (2.24 g, 88%) was isolated as a white powder by filtration.
1H NMR (d6-DMSO): S 11.96, broad s, 1H (COOH); 6 7.42, dd,1H (aryl H); 6 7.33, multiplet, SUBSTITUTE SHEET (RULE 26) 2H (aryl H); 6 7.16, dt, 1H (aryl H); 6 2.97, t, 2H (CH2 a to S); S 2.17, t, (CH2 a to COOH); S
1.6-1.25, complex, l OH (rest of CHZ's).
Exam le 31 -- Preparation of 4- 2-Chloro- hen lsulfan 1-bu ric acid (Compound 31):
[124] Prepared analogously to Compound 30 with 2-chlorobenzenthiol (1 mL, 8.2 mmol), ethyl 4-bromobutyrate (1.3 mL, 8.2 mmol), 45 mL ethyl alcohol, and potassium hydroxide (1.5 g, 27 mmol). The product (0.92 g, 45 %) was isolated by filtration as a white powder. 1H NMR (d6-DMSO): 6 12.1, broad s, 1H (COOH); 6 7.38, multiplet, 2H
(aryl H); S
7.27, dt, 1H (aryl H); 6 7.12, dt, 1H (aryl H); 6 2.96, t, 2H (CH2 a to S); 6 2.33, t, 2H (CH2 a to COOH); 6 1.75, quintet, 2H (remaining CH2).
Example 32 -- Preparation of 6- 3-Chloro- hen isulfan 1-hexanoic acid (Compound 32):
[125] Prepared analogously to Compound 30 with 3-chlorobenzenethiol (1.0 mL, 8.6 mmol), ethyl 6-bromohexanoate (1.5 mL, 8.6 mmol), 45 mL ethyl alcohol, and potassium -hydroxide (1.5 g, 26 mmol). The product (1.9 g, 84 %) was isolated by filtration as a white powder. 1H NMR (d6-DMSO): 6 11.94, broad s, IH (COOH); S 7.28, t, 1H (aryl H);
S 7.26, d, 1H (aryl H); 6 7.2, dt, 1H (aryl H); b 7.16, dt, 1H (aryl H); S 2.95, t, 2H
(CH2 a to S); 6 2.14, t, 2H (CH2 a to COOH); 51.55-1.3, complex, 6H (rest of CH2's).
Example 33 -- Preparation of 8- 4-Chloro- hen lsulfan 1-octanoic acid (Compound 33):
[126] To a 250 mL round bottom flask, equipped with a magnetic stir bar, was added 4-chlorobenzenethiol (5.00 g, 35 mmol), ethyl 8-bromooctanoate (8.68 g, 35 mmol), potassium hydroxide (3.87 g, 69 mmol), and 100 znL methylene chloride. The mixture was stirred at room temperature for 24 hours. The solvent was removed by filtration and the resulting solid was dissolved in 150 mL water. The solution was adjusted to pH 7 with aqueous 1 N
hydrochloric acid. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product (0.20 g, 2%) as an off-white solid, mp 92-93 C.
Found: C: 58.55 %, H:
6.61 % S: 11.41 %, Cl: 12.01%; C1aHa9ClOZS requires C: 58.63 10, H: 6.68 %, S. 11.18 %, Cl:
12.36%; lH NMR (d6-DMSO):67.35, multiplet, 4H (aryl H's); 6 2.95, t, 2H (CH2 a to S); b 2.15, t, 2H (CH2 a to COOH); 6 1.7-1.1, multiplet, I OH (rest of CH2's).
SUBSTITUTE SHEET (RULE 26) Example 34 -- Preparation of 4- 4-Chloro- hen lsulfan 1-bu ric acid (Compound 34 :
[ 127] To a 250 mL round bottom flask, equipped with a magnetic stir bar, was added 4-chlorobenzenethiol (5.00 g, 35 mmol), 4-bromobutyric acid (5.77 g, 35 mmol), potassium hydroxide (1.94 g, 35 mmol), and 100 mL tetrahydrofuran. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered to remove solid byproducts and the solvent was removed under reduced pressure. Crystallization from methyl alcohol:water (3:1) yielded the product (2.10 g, 26%) as an off-white solid, mp 100-101 C. Found:
C: 52.17 %, H:
4.75 % S: 13.53 %, Cl: 15.28%; CIoH11C102S requires C: 52.05 %, H: 4.81 %, S:
13.89 %, Cl:
15.37%; 1H NMR (d6-DMSO): 57.35, multiplet, 4H (aryl H's); b 3.00, t, 2H (CH2 a to S); S
2.40, t, 2H (CH2 a to COOH); 8 1.75, multiplet, 2H (other CH2).
Example 35 -- Preparation of 6- 4-H drox - hen lsulfan 1-hexanoic acid (Compound 35 :
[128] To a 125 mL round bottom flask, equipped with a magnetic stir bar, was added 4-hydroxybenzenethiol (5.00 g, 40 mmol), 6-bromohexanoic acid (7.73 g, 40 mmol), triethylamine (11.08 mL, 79 mmol), and 30 mL tetrahydrofuran. The reaction was stirred at room temperature for 96 hours. The solvent was removed under reduced pressure. The residual was dissolved in water (100 mL) and acidified with aqueous 1 N hydrochloric acid solution to pH
2. The precipitate was collected by filtration. Recrystallization from acetonitrile/water yielded the product (3.10 g, 33%) as an off-white solid, mp 92-94 C. Found: C: 59.88 %, H:
6.62 % S:
13.23 %; C12H1603S requires C: 59.97 %, H: 6.71 %, S: 13.34 %; IH NMR (d6-DMSO): 57.20, multiplet, 2H (aryl H's); 56.75, multiplet, 2H (aryl H's); b 2.80, t, 2H (CH2 a to S); S 2.20, t, 2H
(CHZ a to COOH); S 1.7-1.3, multiplet, 6H (rest of CH2's).
Example 36 -- Preparation of 4- 3-H drox - hen lsulfan 1-bu ric acid (Compound 36):
[129] To a mini-tube equipped with a magnetic stir bar, was added 3-mercaptophenol (0.96 mL, 9.4 mmol), 15 mL ethyl alcohol, 5 mL water, and potassium carbonate (1.6 g, 12 mmol). Ethyl 4-bromobutyrate (1.35 mL, 9.4 mmol) was added drop-wise and the reaction was allowed to stir at room temperature under a nitrogen atmosphere for 20 minutes. Aqueous 1 N
sodium hydroxide solution (28 mL) was added and the reaction was allowed to stir at room temperature for 18 hours. The mixture was heated to 45 C for 3 hours, cooled to room temperature and stirred under a nitrogen atmosphere for 48 hours. Ethyl alcohol was distilled at SUBSTITUTE SHEET (RULE 26) atmospheric pressure and the residue was dissolved in aqueous 1 N sodium hydroxide solution (10 mL) and diluted with 100 mL water. The solution was acidified to pH 1 with aqueous 1 N
hydrochloric acid and cooled to 4 C for 1 hr. The product (1.4 g, 72%) was isolated as a tan solid by filtration. 1H NMR (d6-DMSO): 6 12.0, broad s, 1H (COOH); 8 9.5, broad s, 1H (Ar-OH); S 7.1, t, 1H (aryl H); 6 6.7, multiplet, 2H (aryl H); 6 6.5, dd, 1H (aryl H); S 2.9, t, 2H (CH2 a to S); 6 2.3, t, 2H (CH2 a to COOH); S 1.75, quintet, 2H (remaining of CH2's).
Exam le 37 - Preparation of 843-Hydroxy-pheny 1sulfany 1-octanoic acid (Compound 37):
[130] Prepared analogously to Compound 36 with 3-mercaptophenol (0.85 mL, 8.3 mmol), potassium carbonate (1.4 g, 10.4 mmol), ethyl 8-bromooctanoate (1.75 mL, 8.3 mmol), 15 mL ethyl alcohol, and 5 mL water for first step of reaction. Aqueous 1 N
sodium hydroxide (25 mL, 25 mmol) was used for second reaction step. Crude product was further purified by dissolving in 10 mL aqueous 1 N sodium hydroxide solution and 100 mL water.
The solution was then acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 18 hours.
Product (1.9 g, 84%) was isolated as an off-white powder by filtration. 1H NMR
(d6-DMSO): S
7.3, t, 1H (aryl H); 6 6.65, multiplet, 2H (aryl H); S 6.5, dd, 1H (aryl H), 52.8, t, 2H (CH2 a to S);
6 2.1, t, 2H (CH2 a to COOH); 6 1.5-1.2, complex, lOH (rest ofCH2's).
Example 38 -- Preparation of lU- 4-H drox - hen lsulfan 1-decanoic acid Com ound 38).
[131] Prepared analogously to Compound 36 with 4-hydroxythiophenol (0.76 mL, 6.8 mmol), potassium carbonate (3.7 g, 27 mmol), ethyl 10-bromodecanoate (1.6 mL, 6.Smmo1), 15 mL ethyl alcohol, and 5 mL water for first step of reaction, Aqueous 10 N
sodium hydroxide solution (2.0 mL, 20 mmol) was used for second reaction step.. The product (1.26 g, 63%) was isolated as a tan solid by filtration. 1H NMR (deuterium oxide with NaOD
added): 6 7.0, multiplet, 2H (aryl H); 6 6.4, multiplet, 2H (aryl H); 6 2.6, broad t, 2H (CH2 a to S); 6 1.95, broad t, 2H (CH2 a to COOH); b 2.0-1.0, complex, 14H (rest of CH2's).
Example 39 -- Preparation of 10- 3-H drox -- hen lsulfan 1-decanoic acid (Compound 39 :
[132] Prepared analogously to Compound 36 with 3-mercaptophenol (0.85 mL, 8.3 mmol), potassium carbonate (1.4 g, 10 mmol), ethyl 10-bromodecanoate (2.0 mL, 8.3 mmol), 15 mL ethyl alcohol, and 5 mL water for first step of reaction. Aqueous 1 N
sodium hydroxide SUBSTITUTE SHEET (RULE 26) solution (25 mL, 25 mmol) was used for second reaction step. The crude product was further purified by dissolving in 10 mL of aqueous 1 N sodium hydroxide solution and 100 mL water.
The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 3 hours. Product (2.1 g, 85%) was isolated an off-white solid by filtration. 1H
NMR (d6-DMSO):
8 7.0, t, 1H (aryl H); 6 6.64, multiplet, 2H (aryl H); 6 6.5, dd, IH (aryl H);
S 2.83, t, 21-1(CH2 a to S); S 2.1, t, 2H (CH2 a to COOH); fi 1.5-1.1, complex, l OH (rest of CHZ's).
Example 40 -- Preparation of (2,5-dichloro-phenylsulfanyl)-acetic acid (Compound 40~
[133] To a mini-tube equipped with a magnetic stir bar, was added 2,5-dichlorobenzenethiol (1.1 mL, 8.3 mmol), 20 mL ethyl alcohol, 10 mL water, and potassium hydroxide (1.4 g, 25 mmol). The reaction was stirred under a nitrogen atmosphere for 20 min then ethyl bromoacetate (0.92 mL, 8.3 mmol) was added. The reaction was heated to 45 C for 1 hour. Ethyl alcohol (5 mL) and water (2 mL) were added to dissolve fonned precipitate and the reaction was allowed to stir for 48 hours. Ethyl alcohol was distilled at atmospheric pressure and the residue was dissolved in aqueous 1 N sodium hydroxide solution (10 mL) and diluted with 100 mL water. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 3 days. Product (1.7 g, 88%) was isolated as a white powder by filtration. 1H
NMR (d6-DMSO): 6 7.46, d, 1H (aryl H); 6 7.35, d, IH (aryl H); S 7.23, dd, 1H
(aryl H); S 4.0, s, 2H (CH2).
Example 41 -: Preparation of 6-(2,5-dichloro-phenylsulfan_yl)-hexanoic acid (Compound 41~
[134] Prepared analogously to Compound 40 with 2,5-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 6-bromohexanoate (1.5 mL, 8.3 mmol). Precipitate did not form during initial reaction step;
extra ethyl alcohol and water were not required. Product (2.1 g, 88%) was isolated as a white powder by filtration. 1H NMR (d6-DMOS): S 11.9, broad s, 1H (COOH); 6 7.4, d, IH (aryl H);
6 7.28, d, 1H (aryl H)a 6 7.14, dd, 1H (aryl H); 6 2.95, t, 2H (CH2 a to S); 6 2.1, t, 2H (CHZ a to COOH); 6 1.6-1.3, complex, 6H (rest of CH2's).
SUBSTITUTE SHEET (RULE 26) Example 42 -- Preparation of 3 4-dich.loro- hen yisulfan 1-acetic acid (Compound 42):
[135] Prepared analogously to Compound 40 with 3,4-d.ichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl bromoacetate (0.92 mL, 8.3 mmol). Precipitate did not form during initial reaction step; extra ethyl alcohol and water were not required. Product (1.6 g, 83%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.9, broad s, IH (COOH); b 7.55, d, 1H
(aryl H); b 7.51, d, 1H (aryl H); 8 7.27, dd, 1H (aryl H); S 3.9, s, 2H (CHZ).
Example 43 -- Preparation of b- 3 4-dichloro-hen lsulfan 1-hexanoic acid (Compound 43 :
[136] Prepared analogously to Compound 40 with 3,4-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 6-bromohexanoate (1.5 mL, 8.3 mmol). Precipitate did not form during initial reaction step;
extra ethyl alcohol and water were not required. Product (0.75 g, 31 %) was isolated as a white solid by filtration. 1H NMR (d6-DMSO): S 11.9, s, 1H (COOH); S 7.5, multiplet, 2H (aryl H); b 7.2, dd, 1 H(aryl H); S 2.95, t, 2H (CH2 a to S); S 2.15, t, 2H (CH2'a to COOH); & 1.6-1.3, 6H
(rest of CHZ's).
Example 44 -- Preparation of 3- 2-Chloro- hen lsulfan 1- ra ionic acid (Compound 44):
[137] To a 500 mL round bottom flask, equipped with a magnetic stir bar, was added 2-chlorobenzenethiol (2.00 mL, 18 mmol), ethyl 3-bromopropionate (2.26 mL, 18 mmol), potassium hydroxide (2.08 g, 37 mmol), and 50 mL ethyl alcohol. The reaction mixture was stirred at room temperature for 4 hours, 15 mL water was added and the mixture was stirred for 42 hours at room temperature. Ethyl 3-bromopropionate (1.70 rnL, 13 mmol) and potassium hydroxide (2.19 g, 39 mmol) were added in three aliquots during the next 18 hours. Solvent was removed under reduced pressure. Residual was dissolved in 150 mL water and acidified with aqueous 1 N hydrochloric acid solution to pH 1. Filtration yielded the product (3.56 g, 93%) as a white solid. IH NMR (d6-DMSO): S 12.41, s, 1H (COOH); 6 7.46, dd, 1H (aryl H);
6 7.40, dd, 1H (aryl H); 6 7.34, dt, 1H (aryl H); d 7.20, dt, 1H (aryl H); S 3.18, t, 2H
(CH2 ato S); & 2.59, t, 2H (CH? a to COOH).
SUBSTITUTE SHEET (RULE 26) Example 45 -- Preparation of 3- 3-Chloro- hen lsulfanvl - ro ionic acid (Compound 45 :
[138] Prepared analogously to Compound 44, with 3-chlorobenzenethiol (2.0 mL, mmol), ethyl 3-bromopropionate (2.21 mL, 17 mmol), potassium hydroxide (2.01 g, 36 mmol), 50 mL ethyl alcohol. For aliquots: ethyl3-bromopropionate (1.70 mL, 13 mmol) and potassium hydroxide (2.22 g, 39 mmol) were used. Filtration yielded the product (3.24 g, 88%) as a white solid. 1H NMR (d6-DMSO): S 12.38, s, 1H (COOH); S 7.38, t, 1H (aryl H); 6 7.34, t, IH (aryl H); S 7.28, dt, 1 H (aryl H); & 7.24, dt, I H (aryl H); S 3.18, t, 2H (CH2 a to S); 8 2. 55, t, 2H (CH2 a to COOH).
Exam le 46 -- Preparation of 3-H drox - hen lsulfan 1-acetic acid Com ound 46):
[139] Prepared analogously to Compound 36 with 3-mercaptophenol (1.1 mL, l lmmol), potassium carbonate (1.9 g, 14 mmol), and ethyl bromoacetate (1.2 mL, 11 mmol).
Product did not precipitate from acidic solution. Aqueous acid solution was extracted with ethyl acetate (3 X 50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered to remove drying agent and solvent removed under reduced pressure.
Residual acetic acid was removed by azeotroping with toluene (4 X 100 mL) to yield the product (1.4 g, 70%) as a tan solid. IH NMR (d6-Acetone): 6 7.1, t, 1H (aryl H); S 6.8, multiplet, 2H
(aryl H); 86.6, dd, 1 H (aryl H); b 3.7, s, 2H (CH2).
Example 47 -- Preparation of 2-Fluoro- hen lsulfan 1-acetic acid (Compound 47 [140] Prepared analogously to Compound 40 with 2-fluorothiophenol (1.2 mL, 1lmmol), potassium hydroxide (1.8 g, 32 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl bromoacetate (1.2 mL, l lmmol). Product (1.3 g, 67%) was isolated as a white powder by filtration. IH NMR (d6-DMSO): d 13.0, s, 1 H(COOH); 6 7.38, dt, 1 H(aryl H); 8 7.25-7.1, multiplet, 3H (aryl H); 6 3.8, s, 2H (CHz).
Exam le 48 -- Preparation of 6- 2-Fluoro- hen lsulfan 1-hexanoic acid (Compound 48 :
[141] Prepared analogously to Compound 40 with 2-fluorothiophenol (0.88 mL, 8.2 i,nmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 6-bromohexanoate (1.5 mL, 8.2 mmol). Product (1.8 g. 88%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.0, s, 1H (COOH); S 7.4, dt, 1H (aryl H); S
7.25-7.1, SUBSTITUTE SHEET (RULE 26) multiplet, 3H (aryl H); 8 2.9, t, 2H (CH2 a to S); S 2.1, t, 2H (CHZ a to COOH); S 1.6-1.3, complex, 6H (rest of CH2's).
Example 49 -- Preparation of 6- 3-Fluoro- hen lsulfan 1-hexanoic acid (Compound 49):
[142] Prepared analogously to Compound 40 with 3-fluorothiophenol (0.70 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl 6-bromohexanoate (1.5 mL, 8.3 mmol). Product (1.4 g, 70%) was isolated as a white solid by filtration. 1H NMR (d6-DMSO): 6 12.0, s, 1H (COOH); S 7.3.dt, 1H (aryl H); 6 7.1, dt, 2H (aryl H); 6 6.9, dt, 1H (aryl H); 8 3.0, t, 2H (CH2 a to S); S 2.1, t, 2H (CH2 a to COOH); 6 1.6-1.3, complex, 6H (rest of CH2's).
1-bu ric acid Corn ound 50):
Exam le 50 -- Preparation of 4-(2,5-dichloro-phenylsulfany [143] Prepared analogously to Compound 40 with 2,5-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 4-bromobutyrate (1.2 mL, 8.3 mmol). Reaction was allowed to stir for 8 days under nitrogen atmosphere. Crude product was further purified by dissolving in 3 mL ethyl alcohol and 8 mL
aqueous 1 N sodium hydroxide and allowing to stir under nitrogen atmosphere for 48 hours. The solution was acidified to pH 1 with aqueous 1 N hydrochloric acid and cooled to 4 C for 4 days.
The product (0.49 g, 22%) was isolated as a white solid by filtration. I H NMR
(d6-DMSO): S
12.2, s, 1 H (COOH); 6 7.4, multiplet, 2H (aryl H); 6 7.2, dd, 1 H(aryl H); S
3.0, t, 2H (CH2 a to S); 8 2.35, t, 2H (CH2 a to COOH); S 1.8, quintet, 2H (remaining CH2).
Example 51 -- Preparation of 3-Fluora- hen lsulfan 1-acetic acid (Compound 51 :
[144] Prepared analogously to Compound 40 with 3-fluorothoiphenol (0.9 mL, 11 mmol), potassium hydroxide (1.8 g, 32 mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl bromoacetate (1.2 mL, 11 mmol). The product (0.74 g, 37%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): 6 13.0, broad s,-1H -(COOH); 6 73, dt, 1H (aryl H); S 7.13, multiplet, 2H (aryl H); 6 6.96, dt, 1H (aryl H); 8 3,9, s, 2H (CH2).
SUBSTITUTE SHEET (RULE 26) Example 52 -- Preparation of 4- 3-Fluoro- hen lsulfan 1-bu ric acid (Compound 52):
[145] Prepared analogously to Compound 40 with 3-fluorothiophenol (0.8 mL, 9.4 mmol), potassium hydroxide (1.6 g, 28 mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl 4-bromobutyrate (1.5 mL, 11 mmol). After stirring under a nitrogen atmosphere for 4 days, a seco.nd portion of potassium hydroxide (0.5 g, 9.4 mmol) was added and stirring under a nitrogen atmosphere continued for an additional 18 hours. The product (0.94 g, 47%) was isolated as a white solid by filtration. 1H NMR (d6-DMSO): 6 12.0, s, 1H (COOH); S 7.25, dt, 1H (aryl H); 6 7.1, multiplet, 2H (aryl H); 6 6.9, dt, 1H (aryl H); 2.9, t, 2H (CHZ a to S);
6 2.9, t, 2H (CH2 a to COOH); $ 1.7, quintet, 2H (remaining CH2).
Example 53 -- Preparation of 4- 3 4-dich.loro- hen lsuÃlfan 1-bu ric acid (Compound 53).
[146] Prepared analogously to Compound 50 with 3,4-dichlorobenzenethiol (1.1 mL, 8.3 mmol), potassium hydroxide (1.4 g, 25 mmol), 20 mL ethyl alcohol, 10 mL
water, and ethyl 4-bromobutyrate (1.2 mL, 8.3 mmol). The crade product was further purified by dissolving in 50 mL aqueous I N sodium hydroxide, washing aqueous solution with diethyl ether (3 X 25 mL), acidifying to pH 1 with aqueous 6 N hydrochloric acid and extracting with diethyl ether (3 X 25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered to remove drying agent and the solvent removed under reduced pressure. The residue was dissolved in aqueous I N sodium hydroxide (10 mL), diluted with water (100 mL), acidified to pH 1 using aqueous 1 N hydrochloric acid, and cooled to 4 C for 18 hours. The product (0.73 g, 33%) was isolated as a white powder by filtration. IH NMR (d6-DMSO): & 12.0, broad s, 1H
(COOH); S 7.54, d, 1H (aryl H); 8 7.49, d, 1H (aryl H); 6 7.25, dd, 1H (aryl H); 8 3.0, t, 2H (CH2 a to S); 6 2.3, t, 2H (CH2 a to COOH); S 1.73, quintet, 2H (remaining CH2).
Example 54 -- Preparation of 4- 2-Fluoro- hen lsulfan 1-bu ric acid (Compound 54 :
[147] Prepared analogously to Compound 53 with 2-fluorothiophenol (1.0 mL, 9.4 mmol), potassium hydroxide (1.6 g, 28 mmol), 20 mL ethyl alcohol, 10 mL water, and ethyl 4-bromobutyrate (1.5 mL, 11 mmol). Crude oily product was further purified by dissolving in 40 mL diethyl ether, adding silica-bound maleimide (1,1 g, 14 mmol), and stirring under a nitrogen atmosphere for 20 hours. The silica-bound maleimide scavenger was removed by filtration. The solution was extracted with aqueous 1 N sodium hydroxide solution (2 X 50 mL).
The combined SUBSTITUTE SHEET (RULE 26) aqueous layers were washed with diethyl ether (2 X 50 mL), acidified to pH 1 with aqueous 6 N
hydrochloric acid, and extracted with diethyl ether (2 X 50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered to remove drying agent, and the solvent removed under reduced pressure to yield the product (0.93 g, 46%) as an off-white solid. 1H NMR (d6-DMSO): 6 12.0, s, 1H (COOH); S 7.4, dt, IH (aryl H); 6 7.26-7.1, multiplet, 3H
(aryl H); 5 2.9, t, 2H (CH2 a to COOH); S 2.3, t, 2H (CH2 a to COOH); 1.7, quintet, 2H (remaining CH2).
Example 55 -- Preparation of 4-k'luoro- hen lsulfan 1-acetic acid (Compound 55 :
[148] Prepared analogously to Compound 40 with 4-fluorothiophenol (1.15 mL, 11 mmol), potassium hydroxide (1.8 g, 32 mmol), 20 mL ethyl alcohol, 5 mL water, and ethyl bromoacetate (1.2 mL, 11 nunol). The product (1.4 g, 70%) was isolated as a white powder by filtration. 1H NMR (d6-DMSO): S 12.7, s, IH (COOH); S 7.4, complex, 2H (aryl);
8 7.17, dt, 2H (aryl); S 3.75, s, 2H (CH2).
Example 56 -- Preparation of 4- 4-Fluoro- hen lsulfan 1-bu ric acid Com ound 56 :
[149] Prepared analogously to Compound 40 with 4-fluorothiophenol (1.0 mL, 9.4 mmol), potassium hydroxide (1.6 g, 28 mmol), 20 mL ethyl alcohol, 5 mL water, and ethyl 4-bromobutyrate (1.5 mL, 11 mmol). The reaction was allowed to stir under a nitrogen atmosphere for 18 hours, then potassium hydroxide (0.6 g, 10 mmol) was added and the stirring continued for an additional 48 hours. Ethyl 4-bromobutyrate (0.39 mL, 3 mmol) was added and the reaction was heated to 45 C for 90 minutes. The reaction was cooled to room temperature and allowed to mix under a nitrogen atmosphere for 18 hours. The ethyl alcohol was removed under reduced pressure and the residue was dissolved in aqueous 1N sodium hydroxide (10 mL) and diluted with water (100 mL). The solution was acidified to pH 1 using aqueous 1 N aqueous hydrochloric acid and cooled to 4 C for 18 hours. Filtration yielded the product (1.2 g, 61 %) as an off-white powder. 1H NMR (d-DMSO): 6 12.0, broad s, 1H (COOH); 6 7.35, complex, 2H
(aryl); S 7.13, dt, 2H (aryl); 6 2.9, t, 2H (CH2 a to S); 6 2.3; t, 2H (CH2 a to COOH); 6 1.7, quintet, 2H (remaining CHZ).
SUBSTITUTE SHEET (RULE 26) Example 57 -- Preparation of 6- 4-Fluoro- hen Isulfan 1-hexanoic acid (Compound S7 :
[150] Prepared analogously to Compound 40 with 4-fluorothiophenol (0.88 mL, 8.2 mmol), potassium hydroxide (1.4 g, 24 mmol), 20 mL ethyl alcohol, 5 mL water, and ethyl 6-bromohcxanoate (1.5 mL, 8.2 mmol). Filtration yielded the product (1.8 g, 88%) as a white powder. IH NMR (d6-DMSO): 6 12.0, s, 1 H(COOH); 6 7.37, complex, 2H (aryl); S
7.15, dt, 2H (aryl); S 2.9, t, 2H (CH2 a to S); S 2.17, t, 2H (CH2 a to COOH); 6 1.6-1.3, complex, 6H (rest of CHZ's).
Example 58 -- Preparation of 2 5-Dimeth 1- hen 1sulfan 1-acetic acid (Compound 58), [151] To a 250 mL round bottom flask equipped with a magnetic stir bar was added 2,5-dimethylbenzenethiol (3.5 mL, 25.8 mmol), ethyl bromoacetate (4.32 mL, 25.9 mmol), and 100 mL ethanol. Potassium hydroxide (4.44 g, 79.1 mmol) was added and allowed reaction to mix under nitrogen atmosphere for 18 hours. Water (50 mL) was added and the reaction was allowed to stir for another 18 hours under nitrogen atmosphere. Ethanol was removed under reduced pressure. The remaining solution was diluted with water, acidified to pH 1 with aqueous 1N
hydrochloric acid, and sonicated to form solid precipitate. The solution was cooled to 4 C for 18 hours. Filtered to collect crude product and re-suspended in 1.ON sodium hydroxide. Acidified solution with 1N hydrochloric acid to pH 4.5 and sonicated to form a precipitate. Continued adding 1N hydrochloric acid until pH 1. Solution was cooled to 4 C for 2 - 3 hours. Product (4.44 g, 88%) was isolated by filtration as a gel, mp 73-74 C. Found: C: 61.18 %, H: 6.34 %, S:16.26%; CjoH1202S requires C: 61.2 %, H: 6.16 %, S: 16.34%; 1H NMR (d6-DMSO):
(COOH, not visible due to water in sample); 6 7.09, d. 1H (aryl H); 6 7.06, s, 1H (aryl H); b 6.91, dd, 1H (aryl H); S 3.75, s, 2H (CH2); 6 2.24, s, 6H (aryl-CH3's).
Example 59 -- Preparation of 4- 2-Chloro- hen lsulfan lmeth 1-benzoic acid Com ound 59):
[152] Prepared analogously to Compound 33, but with 2-chloro-benzenethiol, 4-broinomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding SUBSTITUTE SHEET (RULE 26) the product. Found: C: 60.14 %, H: 3.97 % S: 11.42 %, Cl: 12.73 %. C14H1 102SC1 requires C:
60.32%,H:3.98 %, S: 11.50%,Cl: 12.71 %.
Example 60 -- Preparation of 4- 2-Methox - hen lsulfan lmeth l- hen 1-acetic acid (Compound 60):
[153] Prepared analogously to Compound 33, but with 2-methoxy-benzenethiol, (4-bromomethyl-phenyl)-acetic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 66.55 %, H: 5.41 % S: 11.07 %; C16H1603S requires C:
66.64 %, H: 5.59 %, S: 11.12 %.
Example 61 -- Preparation of 4- 2-Meth.ox - hen lsulfan lmeth 1-benzoic acid (Comuound 61):
[1541 Prepared analogously to Compound 33, but with 2-methoxy-benzenethiol, 4-Bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which fonned was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 65.66 %, H: 5.13 % S: 11.40 %; C15H1403S requires C:
65.67 %, H. 5.14 %, S: 11.69 %.
Example 62 -- Pre aration of 4-Phen lsulfan lmeth 1- hen 1-acetic acid (Compound 62 :
[155] Prepared analogously to Compound 33, but with benzenethiol, (4-bromomethyl-phenyl)-acetic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 69.53 %, H: 5.37 % S: 12.51 %; C15H1402S requires C: 69.74 %, H: 5.46 %, S: 12.41 %.
Example 63 -- Preparation of 4-Phen lsulfan lmeth 1-benzoic acid (Compound 63 :
[156] Prepared analogously to Compound 33, but with Benzenethiol, 4-Bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed wxth water (2 X 50 mL) yielding the product.
SUBSTITUTE SHEET (RULE 26) Found: C: 68.06 %, H: 4.91 % S: 12.67 %; C14Hi202S requires C: 68.73 %, H:
4.95 %, S: 13.11 %.
Example 64 Preparation of 4-(4-Chloro-phenylsulfanylmethyl)-benzoic acid (Compound 64)-.
[157] Prepared analogously to Compound 33, but with 4-chloro-benzenethiol, 4-bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 59.90 %, H: 3.92 % S: 11.30 %, Cl: 12.70 %; C14HI1O2SC1 requires C:
60.32 %, H: 3.98 %, S: 11.50 %, Cl: 12.72 %.
Example 65 -- Preparation of 4-(2-Hydroxy-phenylsulfanylmeth_yl)-benzoic acid (Compound 65):
[158] Prepared analogously to Compound 33, but with 2-mercapto-phenol, 4-Bromomethyl-benzoic acid, potassium hydroxide, and 100 mL methylene chloride.
The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 64.75 %, H: 4.88 % S: 11.96 %; C14HI203S requires C:
64.60 %, H: 4.65 %, S: 12.32 %.
Example 66 -- Preparation of 4-(2-Hydroxy-phenylsulfanylmethyl)-benzoic acid (Compound 66):
[159] Prepared analogously to Compound 33, but with 2-mercapto-phenol, (4-bromomethyl-phenyl)-acetic acid, potassium hydroxide, and 100 mL methylene chloride. The precipitate which formed was collected by filtration and washed with water (2 X 50 mL) yielding the product. Found: C: 65.41 %, H: 5.07 % S: 11.92 %; CE5H1403S requires C:
65.67 %, H: 5.14 %,S:11.69%.
Example 67 -- Oral delivery of Insulinto Male Sprague-Dawley Rats [160] Insulin stock solution (15 mg/ml) (Human zinc insulin, Calbiochem-Novabiochem Corp., La Jolla, CA) was prepared with deionized water. Oral dosing SUBSTITUTE SHEET (RULE 26) compositions containing 200 mg/kg of delivery agent compound and 0.5 mglkg of insulin in aqueous solution were prepared with the delivery agent compound shown in Table 1 below.
Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt with one equivalent of sodium hydroxide.
[161] The dosing solution was administered to fasted male Sprague-Dawley rats by oral gavage with an average weight of about 225-250 grams. Blood glucose levels were then determined by glucometer (One Touch UltraLifeScan, Inc.) and compared to vehicle control (1 ml/kg of water). Samples were collected prior to dosing (time 0) and at 15, 30, 45 and 60 minutes after dosing. The % glucose reduction values in Table 1 are values found at the C
minimum, and are an average % reduction with respect to the number of times the experiment was run for each delivery agent.
Table 1: Percent Change in Glucose Insulin 200mg/lcg Delivery Agent Compound; 0.5 rn/k Insulin Delivery % Glucose Delivery % Glucose Comg pouentnd Reduction Com pund Reduction 1 -0.2 28 -51.5 t 27.0 3 -212f9.7 28 -28.2 17.4 3 -25.7 ~ 22.7 28 -46.9 24.9 6 -9.8 f 30.4 29 -51.0 19.4 7 -8.6 t 7.2 29 -56.7 20.5 7 -20.0 29 -69.4 f 11.5 7 -29.0 30 -18.3 39.0 58 -18.2 30 -15.2 f 16.5 9 -6.0 t 12.9 31 -43.3 16.3 9 -34.6 31 -37.4 f 23.8 11 -55.8 7~ 17.9 32 -15.2 28.9 11 -25.8 8.2 36 -69.1 f 5.5 12 -40.2 f25.2 36 -39.4 f 34.9 12 . -54,8 f 46.3 36 -51.3 8.8 12 -35.3 f11.5 40 -6.0 17.5 13 -18.2 t17.4 42 -22.1 5.4 14 -13.9~2.9 44 -7.8f 16.5 14 -47.8f21.2 45 -6.5 21.2 14 -16.9f 16.3 46 0.3f27.7 16 -38.9 f 32.7 47 -31.2 19.4 17 -36.9118.2 47 -38.8-+ 8.7 SUBSTITUTE SHEET (RULE 26) Insulin 200m /k Delivery Agent Com ound; 0.5 m/k g Insulin Delivery % Glucose Delivery % Glucose A Comgeound Reduction C mg pent ound Reduction 17 -46.4 t 8.1 48 -43.1 20.0 17 -39.9 130.0 48 -30.5 :L 22.9 18 -23.5 29.0 48 -32,8 t 16.4 18 -22.5 14.6 49 -34.6 f 11.5 19 -33.6 32.4 49 -17.2 t 23.7 20 -33.9 f 41.8 50 -15.8 :~ 10.6 21 -19.4f6.6 51 -24.9 6.2 22 -3.7 9.4 52 -60.3 + 18.9 23 -67.6 f 6.4 52 -316 22.6 23 -21.015.3 53 -14.817.0 23 -38.4 26.2 54 -37.4 26.0 24 -10A +17.7 55 -20.9 17.5 25 -16.0-L 13.4 56 -4.5~11.1 27 -47.6t17.4 57 -11.0~15.7 [162] 0.5 mg/1Cg of Insulxn and 25 - 100 mg/kg of delivery agent compound (particular amount shown in Table 2 below) was administered to male Sprague-Dawley rats with an average weight of about 225-250 grams. The purpose of this test was to ascertain the dose response of the delivery agent compound. Glucose reduction was determined as set fortb in connection with the data in Table 1.
Table 2: Dose Response of Delivery Aunt Compounds 2, 5, 6 and 8 Delivery Agent Dose Response:
Insulin 0.5 mg/kg Delivery Agent Amount of Delivery % Glucose Compound Agent Compound (mg/kg) Reduction 2 25 -10.0 50 -13.5 5 100 -18.2 6 100 -19.2 6 50 -15.8 8 50 -30.5 8 25 -9.7 SUBSTITUTE SHEET (RULE 26) Insulin Titrations were performed with Delivery Agent 29 in order to gauge the effect of varying dosages of insulin. The results are shown below in Table 3:
Table 3: Insulin Dose Titrations of Delivery A ent Compounds Insulin Titrations:
Delivery Agent 200 mg/kg Delivery Dose of Insulin % Glucose Com Agent (mg/kg) Reduction ound 29 0.50 -30.8 29 0.25 -31.4 29 0.00 -6.8 Example 68 -- Oral and Intracolonic delivery of Heparin to Male S ra ue-Dawle Rats [163] Oral gavage and/or intracoloo.ic (IC) dosing solutions containing delivery agent compound and heparin sodium USP were prepared in 25% aqueous propylene glycol.
Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt with one equivalent of sodium hydroxide. The delivery agent compound and heparin (about 166-182 IU/mg) were mixed by vortex as dry powders. This dry mixture was dissolved in 25% v/v aqueous propylene glycol, vortexed, and placed in a sonicator (about 37 C). The pH
was adjusted to about 7 (6.5 - 8.5) with aqueous NaOH (2N). The dosing solution was sonicated to produce a clear solution. The final volume was adjusted to about 3.0 ml.
The final delivery agent compound dose, and heparin dose are listed in Table 4.
[164] Male Sprague-Dawley rats weighing between about 275-350 g were fasted for 24 hours and anesthetized with ketamine hydrochloride (88 mg/kg) intramuscularly immediately prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals were administered one of the dosing solutions. For oral gavage dosing, an 1 I cm Rusch 8 French catheter was adapted to a I ml syringe with a pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which was then wiped dry. The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger, SUBSTITUTE SHEET (RULE 26) [165] For intracolonic (IC) dosing, a 7.5 cm, 8 French Rusch catheter was adapted to a I
ml syringe with a pipette tip. The dosing catheter was inserted into the colon through the anus until the tube was no longer visible. The dosing solution was expressed slowly into the colon by pressing the syringe plunger.
[166] Citrated blood samples were collected by cardiac puncture following the administration of ketamine (88 mg/kg), typically at 0.25, 0.5, 1.0 and 1.5 hours after dosing.
Heparin absorption was verified by an increase in clotting time measured by the activated partial thromboplastin time (APTT) according to the method of Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods, Philadelphia, PA, W.B. Saunders (1979), which is hereby incorporated by zeference. Previous studies indicated baseline values of about 20 seconds.
Results from the animals in each group were averaged for each time points and the highest of these averages (i.e. mean peak APTT) is reported.
[167] The oral and intracolonic APTT results and plasma heparin concentrations for delivery agents 1, 2, 6, 7, 11, 35 and 59 are shown in Figure 1-3. The following delivery agents were administered as positive controls:
Delivery Agent Structure Notation in Figure o H D.A. õAõ
N
~ OH
H D.A. "Jil """'j OH
OH D.A. ,Wr N N OH
H
SUBSTITUTE SHEET (RULE 26) D.A."L"
O O
N N OH
H
OH D.A. Mõ
I !I
N
H
D.A. "N"
OH
OH O ~
I
~ 0 N
H
Table 4- Intracolonic delivery of Heparin Intracolonic:
Delivery Agent 50 mg/kg; USP Heparin 25 mg/kg Delivery APTT Tmax Agent (seconds) (Minutes) 11 300.0 30.0 35 100.0 30.0 SUBSTITUTE SHEET (RULE 26) Table 5- Oral delivery of Heparin Oral:
Delivery Agent 200 mg/kg; Heparin 80 mg/kg Delivery Agent [Plasma Heparin] Tmax (U/mL) (Minutes) 2 0.5 45 6 0.2 15 1 7 0.7 60 Example 69 -- Oral Delivery of Recombinant Human Growth Hormone (rhGH) to Male Sprnue-Dawley Rats [168] Oral gavage dosing solutions of delivery agent compound and rhGH in phosphate buffer were prepared by mixing. A solution of the delivery agent compound was made either with the sodium salt of the delivery agent compound or by converting the free acid to its sodium salt. A solution of the delivery agent compound was prepared in phosphate buffer and stirred, adding one equivalent of sodium hydroxide (1.0 N) when making the sodium salt.
The final dosing solutions were prepared by mixing the delivery agent compound solution with an rhGH
stock solution (15 mg rhGH/ml glycine and 3.39 mg dibasic sodium phosphate, then diluted with 2% glycerol) with rhGH obtained from Eli Lilly and diluting to the desired volume (usually 3.0 ml). The pH was adjusted, if necessary, to between about 7 and 8.8. The delivery agent compounds and rhGH dose amounts are listed in Table 6.
[169] Male Sprague-Dawley rats weighing about 200-250 g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 xng/kg) 15 minutes prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals was administered one of the dosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with the dosing solution by drawing the solution through the catheter, which was then wiped dry. The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger.
SUBSTITUTE SHEET (RULE 26) [170] Blood samples were collected serially from the tall arterv at time = 15, 30, 45, 60 and 90 minutes. The five samples from each time period were pooled. Serum rhGH
concentrations were quantified by an rhGH immunoassay test kit. Previous studies indicated baseline values of about zero. The maximum concentration at Tmax for each group tested with rhGH is listed.
Table 6- Oral delivery of rhGH
Oral:
Delivery Agent 200 mg/kg; rhGH 3 mg/kg Delivery Serum Level Tmax Agent (ng/rnL) (Minutes) [171] Average serum hGH concentrations over 90 minutes for delivery agent 11 is shown in Figures 4 and 5. The following delivery agents were administered as positive controls:
Delivery Agent Structure Notation in Figure D.A. ~'N
OH
OH O ~
~
\ 0 N
H
0 D.A. "oõ
oH
HO
SUBSTITUTE SHEET (RULE 26) HO ` D. A. "P"
OH
Example 70 -- Oral Delivery of Luteinizing Hormone-Releasing Hormone LHRH to Male Sprague-Dawley Rats [172] Oral gavage dosing solutions of delivery agent compound and LHRH in phosphate buffer were prepared by mixing. A solution of the delivery agent compound was made either with the sodium salt of the delivery agent compound or by converting the free acid to its sodium salt. A solution of the delivery agent compound was prepared in phosphate buffer and stirred, adding one equivalent of sodium hydroxide (1.0 N) when making the sodium salt.
The final dosing solutions were prepared by mixing the delivery agent compound solution with a LHRH stock solution (2.75 ml with a concentration of 20 mg/ml in aqueous solution). The pH
was adjusted, if necessary, to between about 7 and 8.8. The delivery agent compounds and LHRH dose amounts are listed in Table 7.
[173] Male Sprague-Dawley rats weighing between about 250-300 g were fasted foz 24 hours. A dosing group of five animals was administered one of the dosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with the dosing solution by drawing the solution through the catheter, which was then wiped dry.
The catheter was placed down the esophagus leaving 1 em of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger.
[174] Blood samples were collected through retroorbital bleeding of approximately 0.4 ml of blood volume using EDTA tubes at time = 0 (pre-dose), 2, 10, 15 and 30 minutes. The five samples from each time periad were pooled. Previous studies indicated baseline values of about zero. The maximum absorption at the Tmax is reported below in Table 7.
Results for delivery agents 5, 6, 7 and 58 are also shown in Figure 9. As controls, 4-(3-methyl phenoxy) butyric acid (D.A. "B"), the mesylate salt of (4-(8-(2-hydroxyphenoxy)octyl) morpholine (D.A.
SUBSTITUTE SHEET (RULE 26) "C"), 4-(4-(2-hydroxyphcnoxy)butyl) morpholine (D.A. "D"), and 4-(6-(2-hydroxyphenoxy)hexyl) morpholine (D.A. "E") were also administered according to the same protocol and their results are also shown in Figure 6.
Table 7- Oral delivery of LHRH
Oral Absorption of LHRH in Rats Delivery Agent: 200 mglkg; LHRH: 1mg/kg Plasma LHRII
Delivery Tn1ax Agent concentration (Minutes) (ng/mL) Example 71 -- Oral Delivery of Cas ofun in Acetate to Male S ra ue-Dawie Rats [175] Oral gavage dosing solutions of delivery agent compound and caspofungin acetate (Merck & Co., Whitehouse Station, NJ) in phosphate buffer were prepared by mixing. A
solution of the delivery agent compound was made either with the sodium salt of the delivery agent compound or by converting the free acid to its sodium salt. A solution of the delivery agent compound was prepared in phosphate buffer and stirred, adding one equivalent of sodium hydroxide (1.0 N) when making the sodium salt. The final dosing solutions were prepared by mixing the delivery agent compound solution with a caspofungin acetate stock solution (2.5 ml with a concentration of 100 mg/ml in aqueous solution). The pH was adjusted, if necessary, to between about 7 and 8.8. The delivery agent compounds and caspofungin acetate dose amounts are listed in Table 8.
[176] Male Sprague-Dawley rats weighing between about 250-300 g were fasted for 24 hours. A dosing group of five animals was administered one of the dosing solutions. An 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with the dosing solution by drawing the solution through the catheter, which was 'tlien wiped dry.
SUBSTITUTE SHEET (RULE 26) The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger.
[177] Blood samples were collected through retroorbital bleeding at time - 0 (pre-dose), 15, 30, 60, 240, and 480 minutes. The five samples from each time period were pooled.
Previous studies indicated baseline values of about zero. The maximum concentration at the Tmax is reported.
Table 8- Oral delivery of caspofungin acetate Oral caspofungin acetate:
Delivery Agent 200 mglkg; caspofungin acetate: 25 mglk plasma caspofungin Delivery Tmax acetate rnutes Agent concentration ~ ~
(ng/mL) [178] The results for delivery agent 14 is also shown in Figure 10. The delivery agents N-6-2-hydroxy-5-chlorobenzoyl amino hexanoic acid (D.A. "F"), 6-(2-methylformylphenoxy) hexanoic acid (D.A. "E"), 4-(3-methylphenoxy) butyric acid (D.A. "B"), 3-(3-fluoro) propionic acid (D.A. "H"), and 5-phenyl pentanoic acid (D.A. "I") were also administered as controls according to the same protocol and their results are shown in Figure 7.
[179] The above-mentioned patents, applications, test methods, and publications are hereby incorporated by reference in their entirety.
[180] The present invention has been described in details with particular reference to the preferred embodiments thereof, but it will be understood that many variations and modifications of the present invention suggest themselves to those skilled in the art in light of the above detailed description. All such obvious variations and modifications can be affected without departing the spirit and scope of the appended claims of the present invention.
SUBSTITUTE SHEET (RULE 26)
Claims (20)
1. A compound represented by the formula:
wherein A is a branched or unbranched C1-C13 alkylene, C3-C13 arylene group, or a C3-C13 alkyl(arylene) group, R1-R5 are independently a hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group with the proviso that when A is an unsubstituted C1 group, R2 and R3, or R3 and R4 are not both chlorine, or a pharmaceutically acceptable salt thereof.
wherein A is a branched or unbranched C1-C13 alkylene, C3-C13 arylene group, or a C3-C13 alkyl(arylene) group, R1-R5 are independently a hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group with the proviso that when A is an unsubstituted C1 group, R2 and R3, or R3 and R4 are not both chlorine, or a pharmaceutically acceptable salt thereof.
2. A compound selected from the group consisting of:
or pharmaceutically acceptable salts thereof.
or pharmaceutically acceptable salts thereof.
3. A composition comprising:
(A) an active agent; and (B) at least one compound selected from the group consisting of wherein A is a branched or unbranched C1-C13 alkylene, C3-C13 arylene group, or a C3-C13 alkyl(arylene) group, R1-R5 are independently a hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group, or pharmaceutically acceptable salts thereof.
(A) an active agent; and (B) at least one compound selected from the group consisting of wherein A is a branched or unbranched C1-C13 alkylene, C3-C13 arylene group, or a C3-C13 alkyl(arylene) group, R1-R5 are independently a hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, halogen or hydroxy group, or pharmaceutically acceptable salts thereof.
4. A composition comprising:
(A) at least one active agent; and (B) at least one compound selected from the group consisting of or pharmaceutically acceptable salts thereof.
(A) at least one active agent; and (B) at least one compound selected from the group consisting of or pharmaceutically acceptable salts thereof.
5. The composition of claim 3 or 4, wherein the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, and a combination thereof.
6. The composition of claim 5, wherein the biologically active agent is a protein, polypeptide, peptide, hon-none, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.
7. The composition of claim 6, wherein the biologically active agent is selected from the group consisting of: BIBN-4096BS, growth hormones, human growth hormones recombinant human growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone releasing hormones, growth hormone releasing factor, glucagon, interferons, .alpha.-interferon, .beta.-interferon, .gamma.-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin; erythropoietin (EPO), atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoeitin, filgrastim postaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), fragments of PTH, glucagon-like peptide 1 (GLP-1), antimicrobials, anti-fungal agents, vitamins; analogs, fragments, mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds; gallium or gallium salts;
glucagons; zanamivir, sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, caspofungin acetate, CPHPC, RNAi and any combination thereof.
glucagons; zanamivir, sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, caspofungin acetate, CPHPC, RNAi and any combination thereof.
8. The composition of claim 7, wherein the biologically active agent is selected from insulin, leutenizing-hormone releasing hormone, heparin, recombinant human growth hormnone, glucagon, caspofungin acetate, calcitonin, PTH, zanamivir, erythropoietin, analogs, fragments, mimetics and polyethylene glycol (PEG)-modified derivatives of these compounds; and any combination thereof.
9. The composition of claim 7, wherein the biologically active agent comprises insulin.
10. A dosage unit form comprising:
(A) a delivery agent of claims 3 or 4; and (B) an active agent; and (C) (a) an excipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or (h) any combination thereof,
(A) a delivery agent of claims 3 or 4; and (B) an active agent; and (C) (a) an excipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or (h) any combination thereof,
11. The dosage unit form of claim 10, wherein the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, and a combination thereof
12. The dosage unit form of claim 11, wherein the biologically active agent comprises at least one protein, polypeptide, peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, or lipid.
13. The dosage unit form of claim 12, wherein the biologically active agent is selected from the group consisting of: argatroban, BIBN-4096BS, growth hormones, human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, porcine growth hormones, growth hormone releasing hormones, growth hormone releasing factor, interferons, glucagon, .alpha.-interferon, .beta.-interferon, .gamma.-interferon, interleukin-1, interleukin-2, insulin, porcine insulin, bovine insulin, human insulin, human recombinant insulin, insulin-like growth factor, insulin-like growth factor-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin;
erythropoietin, atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoeitin, filgrastim, postaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine, parathyroid hormone, fragments of PTH, glucagon-like peptide 1(GLP-1), antimicrobials, anti-fungal agents, vitamins;
analogs, fragments, mimetics and polyethylene glycol-modified derivatives of these compounds; gallium or gallium salts; glucagons, zanamivir, sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, capsofungin acetate, CPHPC, RNAi and any combination thereof.
erythropoietin, atrial naturetic factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, leutinizing-hormone-releasing-hormone, follicle stimulating hormone, glucocerebrosidase, thrombopoeitin, filgrastim, postaglandins, cyclosporin, vasopressin, cromolyn sodium, sodium chromoglycate, disodium chromoglycate, vancomycin, desferrioxamine, parathyroid hormone, fragments of PTH, glucagon-like peptide 1(GLP-1), antimicrobials, anti-fungal agents, vitamins;
analogs, fragments, mimetics and polyethylene glycol-modified derivatives of these compounds; gallium or gallium salts; glucagons, zanamivir, sumatriptan, almotriptan, naratriptan, rizatriptan, frovatriptan, eletriptan, capsofungin acetate, CPHPC, RNAi and any combination thereof.
14. The dosage unit form of claim 13, wherein the biologically active agent comprises insulin, insulin, Leutenizing-hormone releasing hormone, heparin, Recombinant Human Growth Hormone, glucagon, caspofungin acetate, calcitonin, PTH, zanamivir, erythropoietin or combinations thereof.
15. The dosage unit form of claim 12, wherein the active agent comprises insulin.
16. The dosage unit form of claim 12, wherein the active agent comprises glucagon.
17. The dosage unit form of any of claims 12-18, wherein the dosage unit form comprises a dosing vehicle comprising a tablet, a capsule, a powder, or a liquid.
18. The dosage unit form of claim 19, wherein the dosing vehicle is a liquid selected from the group consisting of water, 1,2-propane diol, ethanol, and any combination thereof.
19. A method for administering a biologically-active agent to an animal in need of the agent, the method comprising administering orally to the animal the composition of any of claims 3-9.
20. A method for preparing a composition comprising mixing:
(A) at least one active agent;
(B) at least one compound of any of claims 1-2; and (C) optionally, a dosing vehicle.
(A) at least one active agent;
(B) at least one compound of any of claims 1-2; and (C) optionally, a dosing vehicle.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US82057206P | 2006-07-27 | 2006-07-27 | |
US60/820,572 | 2006-07-27 | ||
PCT/US2007/074534 WO2008014430A1 (en) | 2006-07-27 | 2007-07-27 | Arylsulfanyl compounds and compositions for delivering active agents |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2672267A1 true CA2672267A1 (en) | 2008-01-31 |
CA2672267C CA2672267C (en) | 2016-05-31 |
Family
ID=38981803
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2672267A Active CA2672267C (en) | 2006-07-27 | 2007-07-27 | Arylsulfanyl compounds and compositions for delivering active agents |
Country Status (6)
Country | Link |
---|---|
US (2) | US9873667B2 (en) |
EP (1) | EP2046736B1 (en) |
JP (1) | JP2010504281A (en) |
CA (1) | CA2672267C (en) |
ES (1) | ES2745411T3 (en) |
WO (1) | WO2008014430A1 (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010504281A (en) * | 2006-07-27 | 2010-02-12 | エミスフェアー・テクノロジーズ・インク | Arylsulfanyl compounds and compositions for delivering active agents |
CN102112157B (en) | 2008-08-06 | 2013-05-29 | 诺沃-诺迪斯克保健股份有限公司 | Conjugated proteins with prolonged in vivo efficacy |
US7906655B2 (en) | 2008-08-07 | 2011-03-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8383094B2 (en) | 2008-10-01 | 2013-02-26 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
TWI504405B (en) | 2009-01-22 | 2015-10-21 | Novo Nordisk Healthcare Ag | Stable growth hormone compounds |
TWI438200B (en) | 2009-02-17 | 2014-05-21 | 必治妥美雅史谷比公司 | Hepatitis c virus inhibitors |
US8394968B2 (en) | 2009-02-17 | 2013-03-12 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8796466B2 (en) | 2009-03-30 | 2014-08-05 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
TW201038559A (en) | 2009-04-09 | 2010-11-01 | Bristol Myers Squibb Co | Hepatitis C virus inhibitors |
US8143414B2 (en) | 2009-04-13 | 2012-03-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8138215B2 (en) | 2009-05-29 | 2012-03-20 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8211928B2 (en) | 2009-05-29 | 2012-07-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8841249B2 (en) | 2009-08-06 | 2014-09-23 | Novo Nordisk A/S | Growth hormones with prolonged in-vivo efficacy |
US20110274648A1 (en) | 2009-11-11 | 2011-11-10 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20110269956A1 (en) | 2009-11-11 | 2011-11-03 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20110281910A1 (en) | 2009-11-12 | 2011-11-17 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US8377980B2 (en) | 2009-12-16 | 2013-02-19 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8362020B2 (en) | 2009-12-30 | 2013-01-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
RU2012134974A (en) | 2010-01-22 | 2014-02-27 | Ново Нордиск Хелс Кеа Аг | STABILIZED GROWTH HORMONE COMPOUND |
CN102834109B (en) | 2010-01-22 | 2016-01-20 | 诺沃—诺迪斯克保健股份有限公司 | Stable growth hormone compound |
CN103269720A (en) | 2010-07-22 | 2013-08-28 | 诺沃—诺迪斯克保健股份有限公司 | Growth hormone conjugates |
WO2012109527A2 (en) * | 2011-02-10 | 2012-08-16 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Class of hdac inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury |
JP6464145B2 (en) | 2013-04-05 | 2019-02-06 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | Growth hormone compound preparation |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2489348A (en) * | 1947-01-15 | 1949-11-29 | Hoffmann La Roche | Production of arylacetic acids and amides |
US3024248A (en) * | 1956-09-18 | 1962-03-06 | Ciba Pharm Prod Inc | Organic sulfur compounds and method for producing same |
US2892852A (en) * | 1957-05-28 | 1959-06-30 | Nathan H Koenig | Alkylthio-, (acetylthio)-and (arylthio)-undecanoic acids |
US2897081A (en) * | 1957-12-30 | 1959-07-28 | Gen Aniline & Film Corp | Antifogging agent and bactericide for photographic emulsions |
AU1175676A (en) * | 1975-03-13 | 1977-09-15 | Carter Wallace | Suppressing histamine release |
US4504484A (en) * | 1982-11-04 | 1985-03-12 | Chevron Research Company | Certain N,N-di-substituted-pyridine carboxamides, fungicidal compositions and fungicidal method of use |
JP2754039B2 (en) * | 1988-06-24 | 1998-05-20 | 塩野義製薬株式会社 | Di-tert-butylhydroxyphenylthio derivative |
JPH0629236B2 (en) * | 1990-05-02 | 1994-04-20 | ナショナル サイエンス カウンシル | 2,6-Dimethoxyhydroquinone-3-mercaptopropionic acid and 2,6-dimethoxyhydroquinone-3-mercaptoacetic acid and their anticancer uses |
US5629020A (en) | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
WO1994023767A1 (en) | 1993-04-22 | 1994-10-27 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
US5443841A (en) | 1992-06-15 | 1995-08-22 | Emisphere Technologies, Inc. | Proteinoid microspheres and methods for preparation and use thereof |
US5401516A (en) | 1992-12-21 | 1995-03-28 | Emisphere Technologies, Inc. | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof |
US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
AU696167B2 (en) * | 1993-10-29 | 1998-09-03 | Trustees Of Boston University | Physiologically stable compositions of butyric acid, and butyric acid salts and derivatives as anti-neoplastic agents |
JPH08127581A (en) * | 1994-01-21 | 1996-05-21 | Sankyo Co Ltd | Disubstituted thiophene compound |
US6011000A (en) * | 1995-03-03 | 2000-01-04 | Perrine; Susan P. | Compositions for the treatment of blood disorders |
US5866536A (en) | 1995-03-31 | 1999-02-02 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
JP3656678B2 (en) * | 1995-08-31 | 2005-06-08 | 株式会社リコー | Reversible thermosensitive coloring composition and reversible recording medium using the same |
US5747537A (en) * | 1995-09-05 | 1998-05-05 | Washington University | Method of inhibiting parasitic activity |
JP2001527517A (en) * | 1996-07-26 | 2001-12-25 | スーザン・ピー・ペリーネ | Therapeutic compositions for blood, viral and cellular diseases |
ES2217425T3 (en) * | 1996-08-07 | 2004-11-01 | Darwin Discovery Limited | DERIVATIVES OF HYDROXAMIC ACID AND CARBOXYL ACID WITH INHIBITORY ACTIVITY OF THE MMP AND TNF. |
DE69737382T2 (en) * | 1996-11-06 | 2007-10-31 | Basilea Pharmaceutica Ag | Vinyl-pyrrolidinone cephalosporin derivatives |
US5973191A (en) * | 1996-12-30 | 1999-10-26 | Vanderbilt University | Selective inhibitors of prostaglandin endoperoxide synthase-2 |
US5776888A (en) | 1997-02-07 | 1998-07-07 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6300514B1 (en) | 1997-06-25 | 2001-10-09 | Ono Pharmaceutical Co., Ltd. | Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient |
WO1999040883A2 (en) * | 1998-02-11 | 1999-08-19 | Faller Douglas V | Compositions and methods for the treatment of cystic fibrosis |
GB9814316D0 (en) | 1998-07-02 | 1998-09-02 | Smithkline Beecham Plc | Novel compounds |
AU5471199A (en) * | 1998-08-07 | 2000-02-28 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
DE19840337A1 (en) * | 1998-09-04 | 2000-03-09 | Hoechst Schering Agrevo Gmbh | Benzoyl derivatives, processes for their preparation and their use as herbicides and plant growth regulators |
CA2358463A1 (en) | 1999-01-08 | 2000-07-13 | Virginia Commonwealth University | Polymeric delivery agents and delivery agent compounds |
AU4145200A (en) | 1999-05-07 | 2000-11-21 | Takeda Chemical Industries Ltd. | Cyclic compounds and uses thereof |
ATE306477T1 (en) * | 1999-06-30 | 2005-10-15 | Lundbeck & Co As H | SELECTIVE NPY (Y5) ANTAGONISTS |
JP3592306B2 (en) * | 2001-03-01 | 2004-11-24 | キヤノン株式会社 | Novel polyhydroxyalkanoate containing a unit having a phenylsulfanyl structure in a side chain, a method for producing the same, a charge control agent containing a novel polyhydroxyalkanoate, a toner binder, a toner, and an image forming method using the toner And image forming apparatus |
JP2002275153A (en) * | 2001-03-16 | 2002-09-25 | Fujirebio Inc | Arylthio derivative |
JP3880444B2 (en) * | 2001-04-27 | 2007-02-14 | キヤノン株式会社 | Novel polyhydroxyalkanoate having a phenylsulfinyl structure and / or phenylsulfonyl structure in the side chain, a method for producing the same, and a charge control agent containing the polyhydroxyalkanoate |
KR100528749B1 (en) * | 2001-04-27 | 2005-11-15 | 캐논 가부시끼가이샤 | Novel polyhydroxyalkanoates having in its side chain phenylsulfinyl structure and/or phenyl sulfonyl structure and production process therefor, charge control agent, toner binder and toner containing same, and image forming method and image forming apparatus using the toner |
AU2002367323A1 (en) | 2001-12-28 | 2003-07-24 | Bayer Pharmaceuticals Corporation | Benzothieno (3,2- |
ITRM20020014A1 (en) | 2002-01-15 | 2003-07-15 | Sigma Tau Ind Farmaceuti | DERIVATIVES OF A-PHENYLTHIOCARBOXYL AND A-PHYLYOXYCARBOXYL ACIDS USEFUL FOR THE TREATMENT OF DISEASES THAT RESPOND TO THE ACTIVATION OF |
IL152904A0 (en) * | 2002-01-24 | 2003-06-24 | Gamida Cell Ltd | Utilization of retinoid and vitamin d receptor antagonists for expansion of renewable stem cell populations |
EP1452605A1 (en) * | 2003-02-27 | 2004-09-01 | Universiteit Utrecht Holding B.V. | Method for determining antiviral activity |
US7687665B2 (en) | 2004-06-24 | 2010-03-30 | Incyte Corporation | 2-methylprop anamides and their use as pharmaceuticals |
JP2010504281A (en) * | 2006-07-27 | 2010-02-12 | エミスフェアー・テクノロジーズ・インク | Arylsulfanyl compounds and compositions for delivering active agents |
-
2007
- 2007-07-27 JP JP2009522014A patent/JP2010504281A/en active Pending
- 2007-07-27 US US12/375,369 patent/US9873667B2/en active Active
- 2007-07-27 EP EP07799859.9A patent/EP2046736B1/en active Active
- 2007-07-27 ES ES07799859T patent/ES2745411T3/en active Active
- 2007-07-27 CA CA2672267A patent/CA2672267C/en active Active
- 2007-07-27 WO PCT/US2007/074534 patent/WO2008014430A1/en active Search and Examination
-
2017
- 2017-12-15 US US15/843,728 patent/US20180334430A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
JP2010504281A (en) | 2010-02-12 |
US20090258817A1 (en) | 2009-10-15 |
US20180334430A1 (en) | 2018-11-22 |
ES2745411T3 (en) | 2020-03-02 |
WO2008014430A1 (en) | 2008-01-31 |
EP2046736B1 (en) | 2019-06-12 |
CA2672267C (en) | 2016-05-31 |
EP2046736A4 (en) | 2011-07-13 |
EP2046736A1 (en) | 2009-04-15 |
US9873667B2 (en) | 2018-01-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2672267C (en) | Arylsulfanyl compounds and compositions for delivering active agents | |
AU2005244904B2 (en) | Compounds and compositions for delivering active agents | |
EP2114145B1 (en) | Phenylalkylcarboxylic acid delivery agents | |
US9035085B2 (en) | Aryl ketone compounds and compositions for delivering active agents | |
US8703821B2 (en) | Dialkyl ether delivery agents | |
AU2006280953B2 (en) | Cyclopropyl compounds and compositions for delivering active agents | |
US8466199B2 (en) | Allyloxy and alkyloxy benzoic acid delivery agents | |
USRE48164E1 (en) | Compounds and compositions for delivering active agents | |
US20100062970A1 (en) | Synthesis of propyl phenoxy ethers and use as delivery agents | |
AU2012200214B2 (en) | Compounds and compositions for delivering active agents | |
AU2012202419B2 (en) | Aryl ketone compounds and compositions for delivering active agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |